👪

Inheritance

1

Polygenic inheritance HP:0010982

Common keratoconus is a complex, polygenic trait: 36 GWAS loci with common variants explaining 12.5% of the genetic variance, with a strong familial aggregation signal (odds ratio 6.42 for a positive family history) but no single Mendelian locus.

Polygenic inheritance

Show evidence (2 references)

PMID:33649486 SUPPORT Human Clinical

"The common variants associated with keratoconus explain 12.5% of the genetic variance"

Quantifies a polygenic common-variant contribution, supporting polygenic rather than Mendelian inheritance.

PMID:9493273 SUPPORT Human Clinical

"Clinical studies provide strong indications of a major role for genes in its etiology."

Corroborates a substantial genetic contribution to keratoconus aetiology.

?

Discussions and Knowledge Gaps

4

Which of the many reported systemic associations of keratoconus are causal, which are confounded by shared exposure (above all eye rubbing), and is the reported inverse association with diabetes mellitus real?

KNOWLEDGE GAP OPEN gap_kc_systemic_associations

Attached to

pathophysiology#Chronic Mechanical Eye Rubbing pathophysiology#Loss of Corneal Biomechanical Rigidity

A dedicated review finds the list of reported systemic associations "very long", with atopy, Down syndrome and connective tissue disease the most frequently cited. These are not mechanistically equivalent: the atopy association is plausibly mediated entirely by itch-driven eye rubbing (already modelled as an environmental factor and a pathophysiology node), the connective-tissue association has direct genetic support in this entry (the GWAS implicates COL12A1, COL6A1, COL1A1 and COL5A1, whose pathogenic variants cause Ehlers-Danlos and osteogenesis imperfecta subtypes), and the Down-syndrome association is quantitatively unresolved (reported prevalences 0-71%). Separately, diabetes mellitus is reported as a candidate *protective* factor - mechanistically attractive because non-enzymatic glycation cross-links stromal collagen, the same chemistry riboflavin/UV-A cross-linking supplies therapeutically - but it is not established. These pairs are candidates for structured kb/comorbidities/ entries once the direction and confounding structure are settled; they are deliberately not asserted as comorbidity entries here.

Proposed experiments

Mediation analysis of the atopy association

exp_kc_atopy_rubbing_mediation

Cohort or Mendelian-randomisation analysis testing whether the atopy-keratoconus association survives adjustment for objectively quantified eye-rubbing exposure.

Decision criterion

Attenuation of the atopy effect to the null after adjustment for rubbing would establish rubbing as the mediator and argue against curating atopy as an independent comorbidity.

Mendelian randomisation of the diabetes inverse association

exp_kc_diabetes_protective_mr

Mendelian randomisation using type 2 diabetes and glycaemic-trait instruments against keratoconus liability, to distinguish a genuine protective effect of glycation cross-linking from detection bias in diabetic eye-care cohorts.

Decision criterion

A significant protective MR estimate consistent in direction with the glycation-cross-linking mechanism would support curating an inverse comorbidity; a null estimate would attribute the observation to surveillance bias.

Show evidence (4 references)

PMID:37374145 SUPPORT Human Clinical

"We found that atopy, Down syndrome, and various connective tissue diseases were the most frequently cited associations in our broad literature search."

Identifies the three most frequently cited systemic associations, which are the subject of this gap.

PMID:37374145 SUPPORT Human Clinical

"Additionally, Diabetes Mellitus has been increasingly studied as a possible protective factor against keratoconus."

States the candidate inverse association while marking it as under study rather than established; typed PARTIAL for that reason.

PMID:37374145 SUPPORT Human Clinical

"However, the mechanisms underlying the development of keratoconus are largely unknown."

Confirms that the mechanistic basis of these associations remains open, justifying KNOWLEDGE_GAP rather than curated comorbidity entries.

+ 1 more reference

What is the primary pathomechanism of keratoconus - is the matrix degradation that thins the stroma driven principally by the polygenic collagen/cell-differentiation susceptibility, by rubbing-induced mechanical and inflammatory injury, or by an obligate interaction of the two?

KNOWLEDGE GAP OPEN gap_kc_primary_pathomechanism

Attached to

pathophysiology#Polygenic Corneal Matrix Susceptibility pathophysiology#Corneal Stromal Extracellular Matrix Degradation

Two authoritative sources published seven years apart both state plainly that the underlying mechanism is unknown, while independently confirming that genetic and environmental contributions both exist. The causal edge from susceptibility to matrix degradation is therefore modelled as INDIRECT_UNKNOWN_INTERMEDIATES. Resolving the relative weight of the two arms determines whether rubbing-cessation counselling is disease-modifying or merely adjunctive, and whether genetic risk stratification could target early cross-linking.

Proposed experiments

Gene-environment interaction cohort

exp_kc_rubbing_prs_interaction

Prospective cohort with objective (not self-reported) eye-rubbing quantification, stratified by polygenic risk score, testing for gene-environment interaction on topographic progression.

Decision criterion

A significant interaction term between rubbing exposure and polygenic risk score on progression rate would support an obligate two-hit model over either arm acting alone.

Tear proteome versus biomechanics time course

exp_kc_tear_proteome_biomechanics_timecourse

Paired tear-proteome and corneal-biomechanics time series in incident cases, to establish whether protease and cytokine elevation precedes or follows measurable biomechanical loss.

Decision criterion

Mediator elevation preceding biomechanical change would place the inflammatory node upstream as a driver rather than a consequence.

Show evidence (2 references)

PMID:24357835 SUPPORT Human Clinical

"The cause and underlying pathological mechanism are unknown, but both environmental and genetic factors are thought to contribute to the development of the disease."

States the knowledge gap explicitly while affirming dual genetic and environmental contribution.

PMID:33649486 SUPPORT Human Clinical

"Keratoconus is characterised by reduced rigidity of the cornea with distortion and focal thinning that causes blurred vision, however, the pathogenetic mechanisms are unknown."

The largest genetic study of the disease still describes the pathogenetic mechanisms as unknown.

Should keratoconus continue to be classified as a "non-inflammatory" corneal ectasia, given consistently elevated tear IL-6, TNF-alpha, and MMP-9?

CONTROVERSY OPEN controversy_kc_inflammatory_status

Attached to

pathophysiology#Ocular Surface Inflammatory Mediator Release

The canonical 1998 definition calls keratoconus a "bilateral noninflammatory corneal ectasia", and that wording persists in textbooks and in the MONDO synonym "noninflammatory corneal thining". Biochemical evidence accumulated since then documents a reproducible cytokine and matrix-metalloproteinase signature in the tear film, and a 2022 review states the condition has more recently been associated with ocular inflammation. The disagreement is substantive rather than semantic: if a low-grade inflammatory arm is causal rather than epiphenomenal, anti-inflammatory or anti-protease therapy becomes a rational adjunct to cross-linking, and this entry's inflammatory-mediator node would move from modulator to driver.

Show evidence (5 references)

PMID:9493273 SUPPORT Human Clinical

"Keratoconus is a bilateral noninflammatory corneal ectasia with an incidence of approximately 1 per 2,000 in the general population."

States the classical non-inflammatory definition.

PMID:25931166 REFUTE Human Clinical

"Recent studies have shown a significant role of proteolytic enzymes, cytokines, and free radicals; therefore, although keratoconus does not meet all the classic criteria for an inflammatory disease, the lack of inflammation has been questioned."

Directly challenges the non-inflammatory classification on biochemical grounds.

PMID:34991971 SUPPORT Human Clinical

"Traditionally, the condition has been described as a noninflammatory disease; however, more recently it has been associated with ocular inflammation."

A contemporary review confirms the classification is actively contested.

+ 2 more references

Can a molecular (non-photochemical) disease-modifying therapy for keratoconus be developed that restores stromal matrix integrity rather than stiffening the residual stroma, and what target should it engage?

OPEN QUESTION OPEN openq_kc_molecular_disease_modifying_therapy

Attached to

pathophysiology#Corneal Stromal Extracellular Matrix Degradation pathophysiology#Loss of Corneal Biomechanical Rigidity

Every established treatment is either photochemical stiffening (CXL), optical compensation (lenses), or tissue replacement (keratoplasty); none reverses the underlying matrix loss. Non-light-based chemical cross-linkers are under investigation as alternatives, which keeps the therapeutic strategy anchored to stiffening rather than matrix restoration. Regenerative approaches - notably limbal or mesenchymal stem-cell exosome cargo aimed at ECM restoration - have been proposed but rest so far on preprint-stage bioinformatic prioritisation rather than peer-reviewed experimental or clinical evidence, so no candidate cargo is asserted in this entry.

Proposed experiments

Peer-reviewed validation of prioritised exosome cargo

exp_kc_exosome_cargo_validation

Experimental validation, in keratoconus corneal tissue and in a model of stromal thinning, of extracellular-vesicle cargo nominated by computational prioritisation from keratoconus transcriptomes.

Decision criterion

Restoration of stromal extracellular-matrix composition and thickness by a defined cargo would establish a matrix-restorative target.

Matrix-restorative candidate versus standard cross-linking

exp_kc_restorative_vs_cxl

Head-to-head comparison of a matrix-restorative candidate against standard epithelium-off cross-linking on corneal biomechanics and topographic progression.

Decision criterion

Non-inferior progression control with superior recovery of corneal thickness would favour a restorative over a stiffening strategy.

Show evidence (1 reference)

PMID:42430076 SUPPORT Other

"In addition, novel chemical cross-linkers are being investigated as non-light-based alternatives for corneal stabilization."

Confirms that the emerging therapeutic pipeline remains oriented towards stabilisation rather than restoration, framing the open question.

⚙

Pathophysiology

14

Polygenic Corneal Matrix Susceptibility

The common form of keratoconus has a polygenic architecture. The first large-scale multi-ethnic GWAS identified 36 genome-wide significant loci and implicated dysregulation of corneal collagen matrix integrity and of cell differentiation pathways as primary disease-causing mechanisms, with common variants explaining 12.5% of the genetic variance. Candidate-gene studies have additionally nominated a heterogeneous set of loci (VSX1, LOX, ZEB1, COL5A1, HGF, ZNF469 and others) whose individual causal validity remains unsettled.

collagen fibril organization GO:0030199 ↕ DYSREGULATED extracellular matrix organization GO:0030198 ↕ DYSREGULATED

corneal stroma UBERON:0001777

Downstream

Corneal Stromal Extracellular Matrix Degradation Genetically encoded weakness of collagen matrix integrity lowers the threshold at which matrix turnover becomes net-catabolic.

Show evidence (2 references)

PMID:33649486 SUPPORT Human Clinical

"We have identified significant association with 36 genomic loci that, for the first time, implicate both dysregulation of corneal collagen matrix integrity and cell differentiation pathways as primary disease-causing mechanisms."

A GWAS of 4,669 cases and 116,547 controls identifies collagen matrix integrity and cell differentiation as the implicated disease mechanisms.

PMID:33649486 SUPPORT Human Clinical

"The common variants associated with keratoconus explain 12.5% of the genetic variance"

Quantifies the polygenic contribution, supporting a susceptibility rather than a Mendelian model for common keratoconus.

Chronic Mechanical Eye Rubbing

Habitual, often vigorous eye rubbing - frequently driven by the itch of atopic conjunctivitis or allergy - is the best-replicated modifiable risk exposure for keratoconus, carrying roughly a three-fold increase in odds. It delivers repetitive mechanical trauma to the corneal surface.

cornea UBERON:0000964

Downstream

Ocular Surface Inflammatory Mediator Release Rubbing acutely raises tear levels of MMP-13, IL-6, and TNF-alpha.

Show evidence (1 reference)

PMID:31498247 SUPPORT Human Clinical

"The odds ratio of eye rubbing, family history of keratoconus, allergy, asthma, and eczema was 3.09 (95% CI: 2.17-4.00), 6.42 (95% CI: 2.59-10.24), 1.42 (95% CI: 1.06-1.79), 1.94 (95% CI: 1.30-2.58), and 2.95 (95% CI: 1.30-4.59), respectively."

A meta-analysis of 29 studies quantifies eye rubbing as an approximately three-fold risk factor, alongside family history and atopy.

Ocular Surface Inflammatory Mediator Release

Despite the traditional "non-inflammatory" label, tears from keratoconus patients consistently show elevated IL-6, TNF-alpha, and MMP-9, and eye rubbing acutely raises MMP-13, IL-6, and TNF-alpha. These mediators supply the proteolytic and cytokine drive for stromal matrix breakdown.

corneal epithelial cell CL:0000575

inflammatory response GO:0006954 ↑ INCREASED

Downstream

Corneal Stromal Extracellular Matrix Degradation Cytokine and matrix-metalloproteinase excess shifts stromal turnover toward net matrix loss.

Show evidence (2 references)

PMID:25931166 SUPPORT Human Clinical

"The majority of studies in the tears of patients with keratoconus have found increased levels of interleukin-6 (IL-6), tumor necrosis factor-α(TNF-α), and matrix metalloproteinase (MMP)-9."

A literature review of biochemical changes documents the tear cytokine and MMP-9 elevation that defines this node.

PMID:25931166 SUPPORT Human Clinical

"Eye rubbing, a proven risk factor for keratoconus, has been also shown recently to increase the tear levels of MMP-13, IL-6, and TNF-α."

Links the mechanical-trauma node upstream to this mediator node by showing that rubbing itself raises the same mediators.

Corneal Oxidative Stress

The keratoconic cornea sits under increased oxidative stress, and that oxidative burden activates the collagenase and gelatinase enzymes that degrade stromal collagen. This is the redox arm of the protease drive modelled downstream, distinct from the cytokine arm supplied by the ocular surface.

keratocyte CL:0002363

response to oxidative stress GO:0006979 ↑ INCREASED

cornea UBERON:0000964

Downstream

Corneal Stromal Extracellular Matrix Degradation Oxidative stress activates collagenase and gelatinase enzymes, supplying the proteolytic activity that degrades stromal collagen.

Show evidence (1 reference)

PMID:38830186 SUPPORT Human Clinical

"Increased oxidative stress leads to the activation of collagenase and gelatinase enzymes."

A review dedicated to keratoconus pathophysiology states the oxidative-stress-to-protease-activation step directly, which is the causal claim this node and its downstream edge encode.

Keratocyte Apoptosis

Increased apoptotic death of keratocytes, the resident stromal cells that synthesise and maintain corneal collagen and proteoglycan, is reported in keratoconus alongside the elevated proinflammatory cytokine profile.

keratocyte CL:0002363

apoptotic process GO:0006915 ↑ INCREASED

corneal stroma UBERON:0001777

Downstream

Progressive Stromal Thinning Depletion of the keratocyte population that synthesises and maintains stromal matrix contributes to net loss of stromal substance. The cited review reports the apoptosis as an observed feature of the disease and does not itself demonstrate this route, hence the indirect typing.

Show evidence (1 reference)

PMID:38830186 SUPPORT Human Clinical

"Elevated levels of proinflammatory cytokines like IL-1b, IL-6, IL-17, and TNF-α have been observed, along with increased apoptosis of keratocytes."

Establishes increased keratocyte apoptosis as a reported cellular feature of keratoconus, co-observed with the tear and stromal cytokine elevation modelled separately.

Corneal Stromal Extracellular Matrix Degradation

An imbalance between degradative enzymes and their proteinase inhibitors in the corneal stroma produces net loss of collagen and proteoglycan matrix. This protease/anti-protease imbalance, together with a possible role for the interleukin-1 system, is the long-standing laboratory candidate for the tissue loss that defines keratoconus.

keratocyte CL:0002363

collagen catabolic process GO:0030574 ↑ INCREASED extracellular matrix disassembly GO:0022617 ↑ INCREASED

corneal stroma UBERON:0001777

Downstream

Progressive Stromal Thinning Sustained net matrix catabolism depletes stromal collagen and reduces corneal thickness.

Anterior Limiting Membrane Rupture Sustained net matrix catabolism breaches Bowman's layer.

Show evidence (1 reference)

PMID:9493273 SUPPORT Human Clinical

"Laboratory studies suggest a role for degradative enzymes and proteinase inhibitors and a possible role for the interleukin-1 system in its pathogenesis, but these roles need to be more clearly defined."

The classic review states the degradative-enzyme/proteinase-inhibitor mechanism, and explicitly flags that it is not yet fully defined.

Progressive Stromal Thinning

Progressive loss of thickness of the central/paracentral corneal stroma, the most consistently reported histopathological finding in keratoconus and the lesion that pentacam/tomographic pachymetry maps clinically.

corneal stroma UBERON:0001777

Downstream

Loss of Corneal Biomechanical Rigidity Reduced stromal thickness reduces the cornea's resistance to intraocular pressure.

Show evidence (2 references)

PMID:34991971 SUPPORT Human Clinical

"Progressive stromal thinning, rupture of the anterior limiting membrane, and subsequent ectasia of the central/paracentral cornea are the most commonly observed histopathological findings."

Names progressive stromal thinning as a commonest histopathological finding and places ectasia downstream of it.

PMID:9493273 SUPPORT Human Clinical

"Classic histopathologic features include stromal thinning, iron deposition in the epithelial basement membrane, and breaks in Bowman's layer."

Independently corroborates stromal thinning as a classic histopathologic feature.

Anterior Limiting Membrane Rupture

Breaks in the anterior limiting membrane (Bowman's layer), the acellular collagenous lamina between the corneal epithelial basement membrane and the stroma. This is a distinct lesion from stromal thinning - a different anatomical substrate - and is reported alongside it as a classic histopathological feature.

anterior limiting lamina of cornea UBERON:0004370

Downstream

Loss of Corneal Biomechanical Rigidity Loss of the Bowman's-layer boundary removes a stiff anterior lamina that may contribute to the cornea's resistance to intraocular pressure. The cited sources establish the lesion, not the biomechanical consequence.

Show evidence (2 references)

PMID:34991971 SUPPORT Human Clinical

"Progressive stromal thinning, rupture of the anterior limiting membrane, and subsequent ectasia of the central/paracentral cornea are the most commonly observed histopathological findings."

Names anterior-limiting-membrane rupture as a commonest histopathological finding, listed as a finding distinct from stromal thinning.

PMID:9493273 SUPPORT Human Clinical

"Classic histopathologic features include stromal thinning, iron deposition in the epithelial basement membrane, and breaks in Bowman's layer."

Independently corroborates breaks in Bowman's layer as a classic histopathologic feature separate from stromal thinning.

Loss of Corneal Biomechanical Rigidity

The thinned, matrix-depleted cornea has reduced rigidity, so normal intraocular pressure produces progressive distortion and focal thinning. This biomechanical failure is the step targeted by collagen cross-linking.

cornea UBERON:0000964

Downstream

Corneal Ectasia and Conical Protrusion A cornea that cannot resist intraocular pressure bulges forward into a cone.

Show evidence (2 references)

PMID:33649486 SUPPORT Human Clinical

"Keratoconus is characterised by reduced rigidity of the cornea with distortion and focal thinning that causes blurred vision, however, the pathogenetic mechanisms are unknown."

Defines reduced corneal rigidity with distortion and focal thinning as the characterising biomechanical abnormality.

PMID:38830186 SUPPORT Human Clinical

"Biomechanical structural failures in the cornea seem to be the primary militating factors in keratoconus etiology and progression."

A dedicated pathophysiology review places biomechanical structural failure as the primary driver of both aetiology and progression, which is the role this node occupies in the pathograph.

Corneal Ectasia and Conical Protrusion

Forward bulging (ectasia) of the central/paracentral cornea into the characteristic cone, producing progressive steepening. This is the defining structural lesion of keratoconus and the substrate for its optical consequences and for acute hydrops.

cornea UBERON:0000964

Downstream

Irregular Astigmatism and Optical Degradation An irregular conical surface refracts light irregularly.

Descemet Membrane Rupture Progressive ectatic stretching predisposes to a break in Descemet membrane.

Show evidence (1 reference)

PMID:34991971 SUPPORT Human Clinical

"Progressive stromal thinning, rupture of the anterior limiting membrane, and subsequent ectasia of the central/paracentral cornea are the most commonly observed histopathological findings."

Places central/paracentral ectasia downstream of the stromal-thinning lesion.

Irregular Astigmatism and Optical Degradation

The irregular conical corneal surface produces irregular astigmatism and higher-order aberration, which spectacles correct poorly and which manifests clinically as progressively blurred, distorted vision.

Show evidence (1 reference)

PMID:34991971 SUPPORT Human Clinical

"Keratoconus is a bilateral and asymmetric disease which results in progressive thinning and steeping of the cornea leading to irregular astigmatism and decreased visual acuity."

States the causal chain from corneal thinning/steepening to irregular astigmatism and reduced visual acuity.

Descemet Membrane Rupture

A break in Descemet membrane, the posterior basement membrane of the cornea. This is the initiating lesion of acute corneal hydrops: it breaches the barrier that normally keeps aqueous humour out of the stroma.

Descemet's membrane UBERON:0004367

Downstream

Stromal Imbibition and Acute Corneal Oedema Loss of the Descemet barrier allows aqueous humour to enter the corneal stroma and epithelium.

Show evidence (1 reference)

PMID:24491416 SUPPORT Human Clinical

"Acute corneal hydrops is an incompletely understood complication of keratoconus, characterized by marked corneal edema caused by a break in Descemet membrane, allowing aqueous to enter the corneal stroma and epithelium."

Identifies the Descemet-membrane break as the lesion that causes the oedema, establishing it as the upstream event.

Stromal Imbibition and Acute Corneal Oedema

Aqueous humour entering the stroma and epithelium through the Descemet break produces the marked corneal oedema that constitutes clinical acute corneal hydrops. It is usually self-limiting, with the oedema resolving over about three months.

corneal stroma UBERON:0001777

Downstream

Corneal Stromal Scarring Resolution of the oedema characteristically leaves a vision-impairing scar.

Show evidence (2 references)

PMID:24491416 SUPPORT Human Clinical

"Acute corneal hydrops is an incompletely understood complication of keratoconus, characterized by marked corneal edema caused by a break in Descemet membrane, allowing aqueous to enter the corneal stroma and epithelium."

Identifies the marked corneal oedema from stromal and epithelial aqueous imbibition as the consequence of the Descemet break.

PMID:24491416 SUPPORT Human Clinical

"Although usually self-limiting, with clinical signs of edema typically resolving after 3 months, it often leaves a vision-impairing scar, necessitating and expediting the need for corneal transplantation."

Establishes the self-limiting course of the oedema and its progression to a vision-impairing scar.

Corneal Stromal Scarring

Permanent stromal scarring - most characteristically as the sequel of resolved acute hydrops - causes irreversible visual impairment and is the common final indication for corneal transplantation.

corneal stroma UBERON:0001777

Show evidence (1 reference)

PMID:24491416 SUPPORT Human Clinical

"Although usually self-limiting, with clinical signs of edema typically resolving after 3 months, it often leaves a vision-impairing scar, necessitating and expediting the need for corneal transplantation."

Establishes post-hydrops scarring as the link between the acute event and the need for keratoplasty.

✶

Histopathology

3

Stromal Thinning

Reduction in corneal stromal thickness, the most consistently reported microscopic finding in keratoconus and the tissue-level correlate of the "Progressive Stromal Thinning" pathophysiology node.

Show evidence (1 reference)

PMID:34991971 SUPPORT Human Clinical

"Progressive stromal thinning, rupture of the anterior limiting membrane, and subsequent ectasia of the central/paracentral cornea are the most commonly observed histopathological findings."

Explicitly names stromal thinning among the most commonly observed histopathological findings.

Breaks in Bowman's Layer

Ruptures of the anterior limiting membrane (Bowman's layer), reported as a classic histopathologic feature and the tissue-level correlate of the "Anterior Limiting Membrane Rupture" pathophysiology node.

Show evidence (1 reference)

PMID:9493273 SUPPORT Human Clinical

"Classic histopathologic features include stromal thinning, iron deposition in the epithelial basement membrane, and breaks in Bowman's layer."

Names breaks in Bowman's layer among the classic histopathologic features of keratoconus.

Iron Deposition in the Epithelial Basement Membrane

Deposition of iron in the corneal epithelial basement membrane, the microscopic basis of the clinically visible Fleischer ring.

Show evidence (1 reference)

PMID:9493273 SUPPORT Human Clinical

"Classic histopathologic features include stromal thinning, iron deposition in the epithelial basement membrane, and breaks in Bowman's layer."

Names epithelial basement-membrane iron deposition among the classic histopathologic features.

⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

●

Phenotypes

7

Eye 2

Keratoconus OBLIGATE HP:0000563

Course: PROGRESSIVE

Show evidence (1 reference)

PMID:34991971 SUPPORT Human Clinical

"Keratoconus is a bilateral and asymmetric disease which results in progressive thinning and steeping of the cornea leading to irregular astigmatism and decreased visual acuity."

Describes the bilateral, asymmetric, progressive corneal thinning and steepening that constitutes the defining phenotype.

Reduced Visual Acuity HP:0007663

Course: PROGRESSIVE

No frequency band is assigned; the cited sources establish visual loss as a characteristic consequence without a quantified proportion.

Show evidence (1 reference)

PMID:24357835 SUPPORT Human Clinical

"Keratoconus (KC) is a common degenerative condition that frequently results in visual loss with an onset typically in early adulthood."

States that keratoconus frequently results in visual loss with early-adulthood onset.

Other 5

Irregular Astigmatism HP:0031792

No frequency band is assigned: the cited review establishes irregular astigmatism as the characteristic optical consequence but does not quantify the proportion of patients affected.

Show evidence (1 reference)

PMID:34991971 SUPPORT Human Clinical

"Keratoconus is a bilateral and asymmetric disease which results in progressive thinning and steeping of the cornea leading to irregular astigmatism and decreased visual acuity."

Directly attributes irregular astigmatism to the corneal thinning and steepening of keratoconus.

Corneal Scarring HP:0000559

Show evidence (1 reference)

PMID:24491416 SUPPORT Human Clinical

"Although usually self-limiting, with clinical signs of edema typically resolving after 3 months, it often leaves a vision-impairing scar, necessitating and expediting the need for corneal transplantation."

Documents vision-impairing scarring as the usual residuum of acute hydrops in keratoconus.

Corneal Stromal Oedema Corneal stromal edema HP:0012040

Temporal: ACUTE

No frequency band is assigned: acute hydrops is a recognised complication of keratoconus but the cited source does not quantify what proportion of patients experience it.

Show evidence (1 reference)

PMID:24491416 SUPPORT Human Clinical

"Acute corneal hydrops is an incompletely understood complication of keratoconus, characterized by marked corneal edema caused by a break in Descemet membrane, allowing aqueous to enter the corneal stroma and epithelium."

Names marked corneal oedema of the stroma and epithelium as the defining clinical finding of acute hydrops in keratoconus.

Corneal Iron Line (Fleischer Ring) HP:6001232

preferred_term uses the clinical eponym; the HPO term is the more general "Corneal iron line", whose own definition names keratoconus as a typical setting. No frequency band is assigned - the cited source lists it as a classic feature without quantifying it.

Show evidence (1 reference)

PMID:9493273 SUPPORT Human Clinical

"Classic histopathologic features include stromal thinning, iron deposition in the epithelial basement membrane, and breaks in Bowman's layer."

Documents epithelial basement-membrane iron deposition as a classic feature of keratoconus.

Vogt striae

No phenotype term is bound because the current local HPO cache has no specific Vogt-striae term. No frequency band is asserted by this source.

Show evidence (1 reference)

PMID:20537579 SUPPORT Human Clinical

"Vogt's striaes, which are fine vertical lines produced by Descemet's membrane compression, is another characteristic sign."

The review directly defines Vogt striae and identifies them as a characteristic keratoconus sign.

🧬

Genetic Associations

10

Polygenic susceptibility architecture

relationship_type: SUSCEPTIBILITY

Show evidence (3 references)

PMID:33649486 SUPPORT Human Clinical

"Here we report the first large scale genome-wide association study of keratoconus including 4,669 cases and 116,547 controls."

Establishes the scale of the GWAS underpinning the polygenic susceptibility model.

PMID:39535071 SUPPORT Human Clinical

"The PRS models demonstrated significant predictive capabilities in EstBB, with the SBayesRC model achieving the highest OR of 2.28 per standard deviation increase in PRS"

A polygenic risk score built from the GWAS predicts keratoconus liability in an independent biobank, which is the operational demonstration that the polygenic architecture recorded here carries real predictive signal rather than being a statistical artefact of the discovery cohort.

PMID:39535071 SUPPORT Human Clinical

"In UKB, we found that adding the best-performing PRS to a model containing corneal measurements increased the AUC from 0.84 to 0.88 (P = 0.012 for difference)"

Shows the polygenic signal adds information beyond corneal measurements, relevant to the potential for genetic risk stratification raised in the primary-pathomechanism knowledge gap.

COL5A1

Gene: COL5A1 hgnc:2209 relationship_type: SUSCEPTIBILITY

Show evidence (2 references)

PMID:33649486 SUPPORT Human Clinical

"9q34.3 9 137412655..137566891 rs3118518 A G 0.270 0.024 1.83E −28 COL5A1,RXRA"

The final trans-ethnic meta-analysis table gives the genome-wide significant COL5A1 association (rs3118518).

PMID:30816092 SUPPORT Human Clinical

"the following candidate variants were selected for genotyping in the Russian population of patients with keratoconus: rs1536482 and rs7044529 in the COL5A1 gene"

A systematic review of keratoconus markers selects COL5A1 variants as prioritised candidates after replication assessment.

HGF

Gene: HGF hgnc:4893 relationship_type: SUSCEPTIBILITY

Show evidence (1 reference)

PMID:30816092 SUPPORT Human Clinical

"rs5745752 and rs2286194 in the HGF gene"

Identifies the prioritised HGF candidate variants for keratoconus genotyping.

VSX1

Gene: VSX1 hgnc:12723 relationship_type: DISPUTED

Show evidence (2 references)

PMID:30816092 SUPPORT Human Clinical

"The analysis included markers in VSX1, SOD1, ZEB1, LOX, CAST, DOCK9, TGFBI, HGF, MAP3K19, KCND3, COL4A3, COL4A4, COL5A1, FNDC3B, FOXO1, BANP-ZNF469, MPDZ-NF1B, WNT10A genes."

VSX1 appears among the analysed candidate markers but was not among the variants prioritised for replication genotyping, consistent with disputed status.

PMID:30816092 SUPPORT Human Clinical

"The studies of causal mutations indicate the genetic heterogeneity of keratoconus, which complicates the development of a diagnostic panel."

Supports the framing that no single candidate gene, VSX1 included, has established causal primacy.

LOX

Gene: LOX hgnc:6664 relationship_type: SUSCEPTIBILITY

Show evidence (2 references)

PMID:33649486 SUPPORT Human Clinical

"5q23.2 5 121269498..121426675 rs840464 T G 0.233 0.025 1.72E −20 SRFBP1,LOX"

The final trans-ethnic meta-analysis table gives the genome-wide significant LOX-locus association (rs840464), an actual association result rather than mere inclusion among analysed markers.

PMID:33649486 SUPPORT Human Clinical

"LOX encodes lysyl oxidase, an enzyme that initiates the cross-linking of collagens and elastin"

Supplies the mechanistic rationale linking the LOX locus to the stromal collagen cross-linking that determines corneal tensile strength.

COL12A1

Gene: COL12A1 hgnc:2188 relationship_type: SUSCEPTIBILITY

Show evidence (1 reference)

PMID:33649486 SUPPORT Human Clinical

"a missense and potentially deleterious variant within COL12A1"

Identifies a genome-wide significant, potentially deleterious COL12A1 missense variant as a keratoconus association.

FNDC3B

Gene: FNDC3B hgnc:24670 relationship_type: SUSCEPTIBILITY

Show evidence (1 reference)

PMID:33649486 SUPPORT Human Clinical

"suppressed levels of FNDC3B, another gene associated with keratoconus in our study"

Names FNDC3B as a keratoconus-associated gene and links it to KLF5-driven corneal epithelial differentiation.

ZNF469

Gene: ZNF469 hgnc:23216 relationship_type: SUSCEPTIBILITY

Show evidence (2 references)

PMID:33649486 SUPPORT Human Clinical

"alleles upstream of the ZNF469 locus that is associated with a higher CCT but an increased risk for keratoconus"

Documents the ZNF469 association and its counterintuitive direction relative to central corneal thickness.

PMID:33649486 SUPPORT Human Clinical

"This supports the view that other mechanisms of loss of corneal integrity and corneal fragility, independent of corneal thickness, contribute to the pathogenesis of keratoconus."

The authors' own interpretation that thickness-independent corneal fragility mechanisms operate, which is why ZNF469 is typed as a susceptibility rather than a thickness-proxy locus.

ALDH3A1

Gene: ALDH3A1 hgnc:405 relationship_type: SUSCEPTIBILITY

Show evidence (1 reference)

PMID:33649486 SUPPORT Human Clinical

"ALDH3A1 encodes a corneal crystallin, a major component of the corneal stroma and epithelium that is upregulated in keratoconus corneas compared to controls"

Links the ALDH3A1 association to a corneal-stroma protein demonstrably dysregulated in keratoconus tissue.

ITGA2

Gene: ITGA2 hgnc:6137 relationship_type: SUSCEPTIBILITY

Show evidence (1 reference)

PMID:33649486 SUPPORT Human Clinical

"The protein encoded by this gene participates in complexes of integrin α2β1, which are collagen receptors"

Gives the collagen-receptor function of the ITGA2 product at the associated locus.

💊

Medical Actions

3

Riboflavin/UV-A Corneal Collagen Cross-Linking

Action: corneal collagen cross-linking (riboflavin/UV-A phototherapy) Ontology label: Phototherapy NCIT:C15301

Agent: riboflavin CHEBI:17015

Corneal collagen cross-linking (CXL) is the established disease-modifying treatment for progressive keratoconus. UV-A photo-activation of riboflavin drives photochemistry that forms covalent cross-links within stromal proteins, reorganising the stroma ultrastructurally and stiffening it, which arrests ectatic progression. In the randomised US multicentre trial maximum keratometry fell by 1.6 D at one year while controls progressed. Protocols have expanded from the original epithelium-off technique to transepithelial approaches.

Mechanism Target:

RESTORES Loss of Corneal Biomechanical Rigidity — Photochemically induced covalent cross-links within stromal proteins stiffen the cornea, directly counteracting the loss of biomechanical rigidity.

Target Phenotypes: Keratoconus HP:0000563

Show evidence (3 references)

PMID:12719068 SUPPORT Human Clinical

"In all treated eyes, the progression of keratoconus was at least stopped."

The original clinical pilot study of riboflavin/UVA cross-linking reports arrest of progression in all treated eyes.

PMID:28495149 SUPPORT Human Clinical

"In the CXL treatment group, the maximum keratometry value decreased by 1.6 diopters (D) from baseline to 1 year, whereas keratoconus continued to progress in the control group."

A prospective randomised sham-controlled multicentre trial demonstrating efficacy against progression.

PMID:42430076 SUPPORT Other

"CXL acts through UV-A photo-activated riboflavin-driven photochemistry that induces covalent cross-links within stromal proteins."

States the molecular mechanism of action linking the treatment to the biomechanical-rigidity node it targets.

Rigid and Scleral Contact Lenses

Optical rehabilitation with rigid gas-permeable or scleral contact lenses masks the irregular corneal surface with a regular refracting interface and remains the mainstay of visual correction in moderate disease. Mild cases may be managed with spectacles alone; failure of scleral lenses is a trigger for surgical management.

Target Phenotypes: Irregular astigmatism HP:0031792 Reduced visual acuity HP:0007663

Show evidence (2 references)

PMID:34991971 SUPPORT Human Clinical

"Mild cases are typically treated with spectacles, moderate cases with contact lenses, while severe cases that cannot be managed with scleral contact lenses may require corneal surgery."

Describes the stepwise optical management and the point at which surgery becomes necessary.

PMID:9493273 SUPPORT Human Clinical

"Contact lenses are the most common treatment modality."

Corroborates contact lenses as the commonest treatment modality.

Corneal Transplantation (Keratoplasty)

Action: corneal transplantation Ontology label: Corneal Transplantation NCIT:C210959

Corneal transplantation is reserved for advanced disease, contact-lens failure, or scarring (notably post-hydrops scarring). Keratoconus is the single most common indication for keratoplasty in the developed world.

Mechanism Target:

BYPASSES Corneal Stromal Scarring — Replacing the scarred, ectatic host cornea with donor tissue bypasses the irreversible structural lesion rather than modifying the disease process.

Target Phenotypes: Corneal scarring HP:0000559

Show evidence (2 references)

PMID:9493273 SUPPORT Human Clinical

"When contact lenses fail, corneal transplant is the best and most successful surgical option."

Positions keratoplasty as the surgical option after contact-lens failure.

PMID:24357835 SUPPORT Human Clinical

"It is the single most common reason for keratoplasty in the developed world."

Quantifies the clinical burden of keratoconus in terms of transplantation demand.

🌍

Environmental Factors

4

Eye rubbing

Habitual mechanical eye rubbing is the best-replicated modifiable environmental risk factor for keratoconus (OR 3.09) and is a target of patient counselling.

Show evidence (1 reference)

PMID:31498247 SUPPORT Human Clinical

"eye rubbing, family history of keratoconus, allergy, asthma, and eczema were the most important risk factors for keratoconus according to the available evidence"

Identifies eye rubbing as among the most important risk factors in the most comprehensive meta-analysis to date.

Mechanism Target:

TRIGGERS Chronic Mechanical Eye Rubbing — The entry models the exposure itself as a node, so this link is an identity rather than a causal step: habitual rubbing and chronic mechanical loading of the cornea are the same thing. Rubbing carries the largest modifiable effect in this disease, which is why counselling to stop is the first intervention.

Show evidence (1 reference)

PMID:31498247 SUPPORT Human Clinical

"eye rubbing, family history of keratoconus, allergy, asthma, and eczema were the most important risk factors for keratoconus according to the available evidence"

Names eye rubbing first among the most important risk factors for keratoconus, the mechanical exposure this node represents.

Atopic diathesis (allergy, asthma, eczema)

Atopic disease raises keratoconus risk (allergy OR 1.42, asthma OR 1.94, eczema OR 2.95), plausibly at least partly through the itch-driven eye rubbing it provokes and through ocular surface inflammation.

Show evidence (1 reference)

PMID:31498247 SUPPORT Human Clinical

"The odds ratio of eye rubbing, family history of keratoconus, allergy, asthma, and eczema was 3.09 (95% CI: 2.17-4.00), 6.42 (95% CI: 2.59-10.24), 1.42 (95% CI: 1.06-1.79), 1.94 (95% CI: 1.30-2.58), and 2.95 (95% CI: 1.30-4.59), respectively."

Quantifies the atopy-associated odds ratios for keratoconus.

Mechanism Target:

PREDISPOSES Chronic Mechanical Eye Rubbing — Atopy acts largely through itch: allergic conjunctivitis provokes the rubbing that damages the cornea. Targeting the rubbing node rather than a corneal node records that indirection, which is why treating the allergy is a way of treating the keratoconus risk.

Show evidence (1 reference)

PMID:31498247 SUPPORT Human Clinical

"The odds ratio of eye rubbing, family history of keratoconus, allergy, asthma, and eczema was 3.09 (95% CI: 2.17-4.00), 6.42 (95% CI: 2.59-10.24), 1.42 (95% CI: 1.06-1.79), 1.94 (95% CI: 1.30-2.58), and 2.95 (95% CI: 1.30-4.59), respectively."

Gives odds ratios for allergy, asthma and eczema alongside eye rubbing, the atopic conditions that provoke rubbing behaviour.

Ultraviolet light exposure

Ultraviolet light exposure is named in the authoritative disease primer, alongside eye rubbing and contact lens wear, as an environmental factor associated with keratoconus progression. The primer states the association with progression; it does not quantify an effect size, and no causal mechanism is asserted here.

Show evidence (1 reference)

PMID:39448666 SUPPORT Human Clinical

"Environmental factors, such as eye rubbing, UV light exposure and contact lens wearing, are associated with disease progression."

The Nature Reviews Disease Primers article names UV light exposure as an environmental factor associated with disease progression.

Mechanism Target:

PREDISPOSES Corneal Oxidative Stress — Ultraviolet exposure is associated with progression and plausibly acts through oxidative damage to the stroma, but the direction is complicated: ultraviolet A with riboflavin is the basis of corneal cross-linking, the standard treatment that halts progression. Dose and cofactors decide which effect dominates.

Show evidence (1 reference)

PMID:39448666 SUPPORT Human Clinical

"Environmental factors, such as eye rubbing, UV light exposure and contact lens wearing, are associated with disease progression."

Names ultraviolet light exposure among the environmental factors associated with disease progression, an association without an identified mediating step.

Contact lens wear

Contact lens wear is named in the disease primer as an environmental factor associated with keratoconus progression. Note the confounding: rigid and scleral lenses are also the mainstay of visual rehabilitation in this entry's treatment section, so lens wear is both an exposure and a consequence of established disease, and the primer does not separate the two.

Show evidence (1 reference)

PMID:39448666 SUPPORT Human Clinical

"Environmental factors, such as eye rubbing, UV light exposure and contact lens wearing, are associated with disease progression."

The Nature Reviews Disease Primers article names contact lens wearing as an environmental factor associated with disease progression.

Mechanism Target:

PREDISPOSES Chronic Mechanical Eye Rubbing — Lens wear reaches this node through the same named intermediate as atopy, irritation provoking rubbing, so it carries the same link type. What is uncertain here is not the intermediate but the direction: lenses are also the commonest treatment for the refractive error keratoconus produces, so wearers are enriched for existing disease. That confounding is why the effect is graded PREDISPOSES rather than anything stronger.

Show evidence (1 reference)

PMID:39448666 SUPPORT Human Clinical

"Environmental factors, such as eye rubbing, UV light exposure and contact lens wearing, are associated with disease progression."

Names contact lens wearing among the environmental factors associated with disease progression, without separating cause from consequence of the disease.

🔬

Diagnosis

2

Corneal topography

Corneal topography is the primary diagnostic modality. Early/subclinical disease is difficult to detect and no single parameter suffices, so topography is combined with corneal pachymetry and higher-order aberration measurement.

Show evidence (2 references)

PMID:34991971 SUPPORT Human Clinical

"Corneal topography is the primary diagnostic tool for keratoconus detection."

Establishes corneal topography as the primary diagnostic tool.

PMID:34991971 SUPPORT Human Clinical

"In incipient cases, however, the use of a single parameter to diagnose keratoconus is insufficient, and in addition to corneal topography, corneal pachymetry and higher order aberration data are now commonly used."

Supports the multi-parameter approach required for incipient disease.

Global Delphi consensus criteria for keratoconus and ectatic disease

There is no single validated gold-standard test. The reference framework for definition, diagnosis, staging and staged management is the Global Delphi consensus. Edition 2 (2026) is the current statement - 128 ophthalmologists from 6 continents, 4 questionnaire rounds plus a face-to-face meeting, two-thirds agreement threshold - superseding the 2015 first edition (36 panelists, 3 rounds), which remains the consensus underlying most of the intervening literature. Both are consensus instruments rather than prospectively validated diagnostic algorithms, and each panel was convened precisely because controversies persist.

Show evidence (4 references)

PMID:42228627 SUPPORT Other

"A significant consensus was reached on topics such as definitions, diagnostic and progression criteria, and management strategies for keratoconus and other ectatic corneal disorders."

The current (Edition 2) consensus is the source of the field's definitions, diagnostic criteria and progression criteria.

PMID:42228627 SUPPORT Other

"This updated Global Consensus provides revised definitions, expert statements, and recommendations for diagnosing and managing keratoconus and other ectatic corneal diseases."

Confirms that Edition 2 revises rather than restates the 2015 definitions, which is why it is cited here as the current framework.

PMID:25738235 SUPPORT Other

"Numerous agreements were generated in definitions, methods of diagnosing, and management of keratoconus and other ectatic diseases."

The 2015 first edition, retained because it is the consensus underlying most of the diagnostic and management literature cited elsewhere here.

+ 1 more reference

📈

Progression

2

Onset and progression

Age: Second to fourth decade

Keratoconus typically develops in the second and third decades and progresses until roughly the fourth decade; the mean age at diagnosis in a nationwide registry was 28.3 years.

Show evidence (2 references)

PMID:34991971 SUPPORT Human Clinical

"Keratoconus normally develops in the second and third decades of life and progresses until the fourth decade."

Gives the characteristic onset and progression window.

PMID:28039037 SUPPORT Human Clinical

"The mean age at diagnosis was 28.3 years and 60.6% of diagnosed patients were male."

Provides the registry-based mean age at diagnosis and a male preponderance among diagnosed patients.

Documented progression (the cross-linking indication)

How "progression" is operationalised is the decision point for offering cross-linking, and the literature has no unified criterion. A systematic review of 221 articles found anterior-curvature data used in 97.8%, with maximum keratometry (Kmax) the single most frequent criterion (85.5%), followed by refractive astigmatism and thinnest-point pachymetry; progression was assessed over a 6- to 12-month follow-up in 64.7%. Posterior corneal data were used in only 8.1% of studies and epithelial data in none, so the criteria in common use underexploit available tomography. The Global Delphi consensus in the diagnosis section is the corresponding expert statement; this record captures what the primary literature actually uses.

Show evidence (3 references)

PMID:39671084 SUPPORT Human Clinical

"the most frequent criterion used was maximum keratometry (Kmax), used in 85.5% (189/221) of the articles"

Identifies Kmax as the dominant operational criterion for progression across the reviewed literature.

PMID:39671084 SUPPORT Human Clinical

"Progression was assessed between 6- and 12-month follow-up in 64.7% (143/221) of the articles."

Gives the follow-up interval over which progression is conventionally assessed.

PMID:39671084 SUPPORT Human Clinical

"The present study demonstrates the lack of unified criteria to define progression of keratoconus and an underutilization of the technology described."

Qualifies the record: the criteria above are the most common ones, not an agreed standard. Typed PARTIAL because it constrains rather than establishes the progression definition.

📊

Prevalence

4

Worldwide

Point Prevalence 138.0 per 100,000 (114.0–162.0) >1 in 1,000

Meta-analysis of 29 studies covering 7,158,241 participants from 15 countries: 1.38 per 1000 (95% CI 1.14-1.62 per 1000), i.e. 138 per 100,000.

Show evidence (1 reference)

PMID:31498247 SUPPORT Human Clinical

"The prevalence of keratoconus in the whole population was 1.38 per 1000 population"

Provides the pooled worldwide prevalence estimate normalised here to 138 per 100,000.

Netherlands (nationwide health-insurance database, 4.4 million patients)

Point Prevalence 265.0 per 100,000 (260.0–270.0) >1 in 1,000

Registry-based estimate in the era of modern topographic diagnostics (1:375); the authors note this is 5- to 10-fold higher than older population-study estimates, so the worldwide meta-analytic figure above and this one are not directly comparable.

Show evidence (1 reference)

PMID:28039037 SUPPORT Human Clinical

"the estimated prevalence of keratoconus in the general population was 1:375 (265 cases per 100 000, 95% CI: 260-270)"

Gives the nationwide registry prevalence estimate normalised to 265 per 100,000.

Netherlands, ages 10-40 years

Annual Incidence 13.3 per 100,000 (11.6–15.2)

Annual incidence of newly diagnosed keratoconus in the age band in which it typically presents (13.3 cases per 100,000, 95% CI 11.6-15.2). No prevalence_class is asserted: the Orphanet classes are prevalence bands and applying one to an incidence measure would conflate the two.

Show evidence (1 reference)

PMID:28039037 SUPPORT Human Clinical

"The annual incidence of keratoconus was 1:7500 in the relevant age category"

Provides the age-specific annual incidence used for this record.

Persons with Down syndrome

Point Prevalence Unknown

Keratoconus is markedly over-represented in Down syndrome, but reported prevalences range from 0% to 71% across 20 studies of widely varying design and quality, so no numeric rate is asserted here. Screening in this group should be considered.

Show evidence (1 reference)

PMID:33981858 SUPPORT Human Clinical

"The present review showed that the prevalence of keratoconus in persons with Down syndrome is higher than in the general population. However, estimates from previous studies vary widely."

Supports elevated but imprecisely quantified prevalence in Down syndrome.

{ }

Source YAML

click to show

name: Keratoconus
creation_date: "2026-07-30T00:00:00Z"
category: Complex
disease_term:
  preferred_term: keratoconus
  term:
    id: MONDO:0015486
    label: keratoconus
description: >
  Keratoconus is the most common corneal ectatic disorder: a bilateral,
  typically asymmetric condition in which the central/paracentral cornea
  progressively thins, loses biomechanical rigidity, and bulges forward into a
  cone. Onset is usually in the second-to-third decade with progression until
  about the fourth decade, and the resulting irregular astigmatism and
  higher-order aberration produce blurred vision that spectacles correct poorly.
  Aetiology is multifactorial: a polygenic susceptibility implicating corneal
  collagen matrix integrity and cell differentiation pathways interacts with
  environmental exposures, above all chronic mechanical eye rubbing and the
  atopic diathesis. Although classically labelled "non-inflammatory", tear-film
  studies consistently find elevated IL-6, TNF-alpha, and MMP-9, and a
  protease/anti-protease imbalance is a leading candidate for the stromal
  matrix loss; increased oxidative stress activating collagenase and gelatinase
  is the parallel redox arm of that same protease drive, and increased
  keratocyte apoptosis is reported alongside it. Acute corneal hydrops - a break in Descemet membrane with
  stromal imbibition of aqueous - is a characteristic complication that usually
  resolves but leaves a vision-limiting scar. Riboflavin/UV-A corneal
  collagen cross-linking is the established disease-modifying therapy for
  progressive disease; visual rehabilitation relies on rigid or scleral contact
  lenses, and corneal transplantation is reserved for advanced or scarred
  corneas.
parents:
- Corneal disorder
- Corneal ectatic disorder
synonyms:
- KC
- Conical cornea
- Noninflammatory corneal thinning
references:
- reference: PMID:34991971
  title: "Keratoconus: An updated review."
- reference: PMID:24357835
  title: "The pathogenesis of keratoconus."
- reference: PMID:33649486
  title: "A multi-ethnic genome-wide association study implicates collagen matrix integrity and cell differentiation pathways in keratoconus."
- reference: PMID:42228627
  title: "Global Consensus on Keratoconus and Ectatic Diseases-Edition 2."
- reference: PMID:25738235
  title: "Global consensus on keratoconus and ectatic diseases."
- reference: PMID:37374145
  title: "Systemic Associations with Keratoconus."
- reference: PMID:9493273
  title: "Keratoconus."
- reference: PMID:38830186
  title: "The Pathophysiology of Keratoconus."
- reference: PMID:39448666
  title: "Keratoconus."
- reference: PMID:39671084
  title: "Definition of Progressive Keratoconus: A Systematic Review."
- reference: PMID:39535071
  title: "Developing and validating a comprehensive polygenic risk score to enhance keratoconus risk prediction."
notes: >-
  MONDO:0015486 carries an HP xref (HP:0000563), reflecting that keratoconus is
  a "disease-like phenotype" - it is both a curated disease entry here and the
  HPO phenotype term used by other entries (e.g. syndromic keratoconus in Down
  syndrome, Leber congenital amaurosis, and connective-tissue disorders). MONDO
  additionally lists two Orphanet cross-references (Orphanet:2335 and
  Orphanet:156071) and the OMIM phenotypic series OMIMPS:148300; no single
  Mendelian locus accounts for the common disease.
pathophysiology:
- name: Polygenic Corneal Matrix Susceptibility
  biological_scale: MOLECULAR
  description: >
    The common form of keratoconus has a polygenic architecture. The first
    large-scale multi-ethnic GWAS identified 36 genome-wide significant loci and
    implicated dysregulation of corneal collagen matrix integrity and of cell
    differentiation pathways as primary disease-causing mechanisms, with common
    variants explaining 12.5% of the genetic variance. Candidate-gene studies
    have additionally nominated a heterogeneous set of loci (VSX1, LOX, ZEB1,
    COL5A1, HGF, ZNF469 and others) whose individual causal validity remains
    unsettled.
  biological_processes:
  - preferred_term: collagen fibril organization
    term:
      id: GO:0030199
      label: collagen fibril organization
    modifier: DYSREGULATED
  - preferred_term: extracellular matrix organization
    term:
      id: GO:0030198
      label: extracellular matrix organization
    modifier: DYSREGULATED
  locations:
  - preferred_term: corneal stroma
    term:
      id: UBERON:0001777
      label: substantia propria of cornea
  downstream:
  - target: Corneal Stromal Extracellular Matrix Degradation
    description: >
      Genetically encoded weakness of collagen matrix integrity lowers the
      threshold at which matrix turnover becomes net-catabolic.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  evidence:
  - reference: PMID:33649486
    reference_title: "A multi-ethnic genome-wide association study implicates collagen matrix integrity and cell differentiation pathways in keratoconus."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We have identified significant association with 36 genomic loci that, for
      the first time, implicate both dysregulation of corneal collagen matrix
      integrity and cell differentiation pathways as primary disease-causing
      mechanisms.
    explanation: >-
      A GWAS of 4,669 cases and 116,547 controls identifies collagen matrix
      integrity and cell differentiation as the implicated disease mechanisms.
  - reference: PMID:33649486
    reference_title: "A multi-ethnic genome-wide association study implicates collagen matrix integrity and cell differentiation pathways in keratoconus."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The common variants associated with keratoconus explain 12.5% of the genetic variance"
    explanation: >-
      Quantifies the polygenic contribution, supporting a susceptibility rather
      than a Mendelian model for common keratoconus.
- name: Chronic Mechanical Eye Rubbing
  biological_scale: ORGANISM
  description: >
    Habitual, often vigorous eye rubbing - frequently driven by the itch of
    atopic conjunctivitis or allergy - is the best-replicated modifiable risk
    exposure for keratoconus, carrying roughly a three-fold increase in odds. It
    delivers repetitive mechanical trauma to the corneal surface.
  notes: >-
    No biological_processes term is asserted. Eye rubbing is an organism-scale
    behaviour, not a molecular or cellular process, so a GO term does not
    belong on this node; the cellular response it provokes is captured
    downstream on "Ocular Surface Inflammatory Mediator Release".
  locations:
  - preferred_term: cornea
    term:
      id: UBERON:0000964
      label: cornea
  downstream:
  - target: Ocular Surface Inflammatory Mediator Release
    description: >
      Rubbing acutely raises tear levels of MMP-13, IL-6, and TNF-alpha.
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:31498247
    reference_title: "The Prevalence and Risk Factors for Keratoconus: A Systematic Review and Meta-Analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The odds ratio of eye rubbing, family history of keratoconus, allergy,
      asthma, and eczema was 3.09 (95% CI: 2.17-4.00), 6.42 (95% CI:
      2.59-10.24), 1.42 (95% CI: 1.06-1.79), 1.94 (95% CI: 1.30-2.58), and 2.95
      (95% CI: 1.30-4.59), respectively.
    explanation: >-
      A meta-analysis of 29 studies quantifies eye rubbing as an approximately
      three-fold risk factor, alongside family history and atopy.
- name: Ocular Surface Inflammatory Mediator Release
  biological_scale: CELLULAR
  description: >
    Despite the traditional "non-inflammatory" label, tears from keratoconus
    patients consistently show elevated IL-6, TNF-alpha, and MMP-9, and eye
    rubbing acutely raises MMP-13, IL-6, and TNF-alpha. These mediators supply
    the proteolytic and cytokine drive for stromal matrix breakdown.
  biological_processes:
  - preferred_term: inflammatory response
    term:
      id: GO:0006954
      label: inflammatory response
    modifier: INCREASED
  cell_types:
  - preferred_term: corneal epithelial cell
    term:
      id: CL:0000575
      label: corneal epithelial cell
  downstream:
  - target: Corneal Stromal Extracellular Matrix Degradation
    description: >
      Cytokine and matrix-metalloproteinase excess shifts stromal turnover
      toward net matrix loss.
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:25931166
    reference_title: "Keratoconus: an inflammatory disorder?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The majority of studies in the tears of patients with keratoconus have
      found increased levels of interleukin-6 (IL-6), tumor necrosis
      factor-α(TNF-α), and matrix metalloproteinase (MMP)-9.
    explanation: >-
      A literature review of biochemical changes documents the tear cytokine and
      MMP-9 elevation that defines this node.
  - reference: PMID:25931166
    reference_title: "Keratoconus: an inflammatory disorder?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Eye rubbing, a proven risk factor for keratoconus, has been also shown
      recently to increase the tear levels of MMP-13, IL-6, and TNF-α.
    explanation: >-
      Links the mechanical-trauma node upstream to this mediator node by showing
      that rubbing itself raises the same mediators.
- name: Corneal Oxidative Stress
  biological_scale: CELLULAR
  description: >
    The keratoconic cornea sits under increased oxidative stress, and that
    oxidative burden activates the collagenase and gelatinase enzymes that
    degrade stromal collagen. This is the redox arm of the protease drive
    modelled downstream, distinct from the cytokine arm supplied by the ocular
    surface.
  notes: >-
    No upstream edge is asserted into this node. The cited review states that
    oxidative stress activates the degradative enzymes but does not establish
    what initiates the oxidative stress in keratoconus, so it is modelled as an
    independent contributor rather than placed downstream of rubbing or of the
    inflammatory-mediator node.
  biological_processes:
  - preferred_term: response to oxidative stress
    term:
      id: GO:0006979
      label: response to oxidative stress
    modifier: INCREASED
  cell_types:
  - preferred_term: keratocyte
    term:
      id: CL:0002363
      label: keratocyte
  locations:
  - preferred_term: cornea
    term:
      id: UBERON:0000964
      label: cornea
  downstream:
  - target: Corneal Stromal Extracellular Matrix Degradation
    description: >
      Oxidative stress activates collagenase and gelatinase enzymes, supplying
      the proteolytic activity that degrades stromal collagen.
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:38830186
    reference_title: "The Pathophysiology of Keratoconus."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Increased oxidative stress leads to the activation of collagenase and gelatinase enzymes."
    explanation: >-
      A review dedicated to keratoconus pathophysiology states the
      oxidative-stress-to-protease-activation step directly, which is the causal
      claim this node and its downstream edge encode.
- name: Keratocyte Apoptosis
  biological_scale: CELLULAR
  description: >
    Increased apoptotic death of keratocytes, the resident stromal cells that
    synthesise and maintain corneal collagen and proteoglycan, is reported in
    keratoconus alongside the elevated proinflammatory cytokine profile.
  notes: >-
    No upstream edge from "Ocular Surface Inflammatory Mediator Release" is
    asserted. The cited review reports the cytokine elevation and the keratocyte
    apoptosis as co-observed features ("along with"), which does not establish
    that the cytokines cause the apoptosis; asserting that edge would overstate
    the source.
  biological_processes:
  - preferred_term: apoptotic process
    term:
      id: GO:0006915
      label: apoptotic process
    modifier: INCREASED
  cell_types:
  - preferred_term: keratocyte
    term:
      id: CL:0002363
      label: keratocyte
  locations:
  - preferred_term: corneal stroma
    term:
      id: UBERON:0001777
      label: substantia propria of cornea
  downstream:
  - target: Progressive Stromal Thinning
    description: >
      Depletion of the keratocyte population that synthesises and maintains
      stromal matrix contributes to net loss of stromal substance. The cited
      review reports the apoptosis as an observed feature of the disease and
      does not itself demonstrate this route, hence the indirect typing.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  evidence:
  - reference: PMID:38830186
    reference_title: "The Pathophysiology of Keratoconus."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Elevated levels of proinflammatory cytokines like IL-1b, IL-6, IL-17, and
      TNF-α have been observed, along with increased apoptosis of keratocytes.
    explanation: >-
      Establishes increased keratocyte apoptosis as a reported cellular feature
      of keratoconus, co-observed with the tear and stromal cytokine elevation
      modelled separately.
- name: Corneal Stromal Extracellular Matrix Degradation
  biological_scale: TISSUE
  description: >
    An imbalance between degradative enzymes and their proteinase inhibitors in
    the corneal stroma produces net loss of collagen and proteoglycan matrix.
    This protease/anti-protease imbalance, together with a possible role for the
    interleukin-1 system, is the long-standing laboratory candidate for the
    tissue loss that defines keratoconus.
  cell_types:
  - preferred_term: keratocyte
    term:
      id: CL:0002363
      label: keratocyte
  biological_processes:
  - preferred_term: collagen catabolic process
    term:
      id: GO:0030574
      label: collagen catabolic process
    modifier: INCREASED
  - preferred_term: extracellular matrix disassembly
    term:
      id: GO:0022617
      label: extracellular matrix disassembly
    modifier: INCREASED
  locations:
  - preferred_term: corneal stroma
    term:
      id: UBERON:0001777
      label: substantia propria of cornea
  downstream:
  - target: Progressive Stromal Thinning
    description: >
      Sustained net matrix catabolism depletes stromal collagen and reduces
      corneal thickness.
    causal_link_type: DIRECT
  - target: Anterior Limiting Membrane Rupture
    description: >
      Sustained net matrix catabolism breaches Bowman's layer.
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:9493273
    reference_title: "Keratoconus."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Laboratory studies suggest a role for degradative enzymes and proteinase
      inhibitors and a possible role for the interleukin-1 system in its
      pathogenesis, but these roles need to be more clearly defined.
    explanation: >-
      The classic review states the degradative-enzyme/proteinase-inhibitor
      mechanism, and explicitly flags that it is not yet fully defined.
- name: Progressive Stromal Thinning
  biological_scale: TISSUE
  description: >
    Progressive loss of thickness of the central/paracentral corneal stroma,
    the most consistently reported histopathological finding in keratoconus and
    the lesion that pentacam/tomographic pachymetry maps clinically.
  locations:
  - preferred_term: corneal stroma
    term:
      id: UBERON:0001777
      label: substantia propria of cornea
  downstream:
  - target: Loss of Corneal Biomechanical Rigidity
    description: >
      Reduced stromal thickness reduces the cornea's resistance to intraocular
      pressure.
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:34991971
    reference_title: "Keratoconus: An updated review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Progressive stromal thinning, rupture of the anterior limiting membrane,
      and subsequent ectasia of the central/paracentral cornea are the most
      commonly observed histopathological findings.
    explanation: >-
      Names progressive stromal thinning as a commonest histopathological
      finding and places ectasia downstream of it.
  - reference: PMID:9493273
    reference_title: "Keratoconus."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Classic histopathologic features include stromal thinning, iron
      deposition in the epithelial basement membrane, and breaks in Bowman's
      layer.
    explanation: >-
      Independently corroborates stromal thinning as a classic histopathologic
      feature.
- name: Anterior Limiting Membrane Rupture
  biological_scale: TISSUE
  description: >
    Breaks in the anterior limiting membrane (Bowman's layer), the acellular
    collagenous lamina between the corneal epithelial basement membrane and the
    stroma. This is a distinct lesion from stromal thinning - a different
    anatomical substrate - and is reported alongside it as a classic
    histopathological feature.
  notes: >-
    The downstream edge to biomechanical rigidity is typed
    INDIRECT_UNKNOWN_INTERMEDIATES rather than DIRECT. Both cited snippets
    enumerate Bowman's-layer breaks as a histopathological finding; neither
    demonstrates a biomechanical consequence. The standard counter-observation
    is that Bowman's layer is ablated wholesale in photorefractive keratectomy
    without inducing ectasia, which argues its independent structural
    contribution is modest.
  locations:
  - preferred_term: anterior limiting lamina of cornea
    term:
      id: UBERON:0004370
      label: anterior limiting lamina of cornea
  downstream:
  - target: Loss of Corneal Biomechanical Rigidity
    description: >
      Loss of the Bowman's-layer boundary removes a stiff anterior lamina that
      may contribute to the cornea's resistance to intraocular pressure. The
      cited sources establish the lesion, not the biomechanical consequence.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  evidence:
  - reference: PMID:34991971
    reference_title: "Keratoconus: An updated review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Progressive stromal thinning, rupture of the anterior limiting membrane,
      and subsequent ectasia of the central/paracentral cornea are the most
      commonly observed histopathological findings.
    explanation: >-
      Names anterior-limiting-membrane rupture as a commonest histopathological
      finding, listed as a finding distinct from stromal thinning.
  - reference: PMID:9493273
    reference_title: "Keratoconus."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Classic histopathologic features include stromal thinning, iron
      deposition in the epithelial basement membrane, and breaks in Bowman's
      layer.
    explanation: >-
      Independently corroborates breaks in Bowman's layer as a classic
      histopathologic feature separate from stromal thinning.
- name: Loss of Corneal Biomechanical Rigidity
  biological_scale: TISSUE
  description: >
    The thinned, matrix-depleted cornea has reduced rigidity, so normal
    intraocular pressure produces progressive distortion and focal thinning.
    This biomechanical failure is the step targeted by collagen cross-linking.
  locations:
  - preferred_term: cornea
    term:
      id: UBERON:0000964
      label: cornea
  downstream:
  - target: Corneal Ectasia and Conical Protrusion
    description: >
      A cornea that cannot resist intraocular pressure bulges forward into a
      cone.
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:33649486
    reference_title: "A multi-ethnic genome-wide association study implicates collagen matrix integrity and cell differentiation pathways in keratoconus."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Keratoconus is characterised by reduced rigidity of the cornea with
      distortion and focal thinning that causes blurred vision, however, the
      pathogenetic mechanisms are unknown.
    explanation: >-
      Defines reduced corneal rigidity with distortion and focal thinning as the
      characterising biomechanical abnormality.
  - reference: PMID:38830186
    reference_title: "The Pathophysiology of Keratoconus."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Biomechanical structural failures in the cornea seem to be the primary
      militating factors in keratoconus etiology and progression.
    explanation: >-
      A dedicated pathophysiology review places biomechanical structural failure
      as the primary driver of both aetiology and progression, which is the role
      this node occupies in the pathograph.
- name: Corneal Ectasia and Conical Protrusion
  biological_scale: TISSUE
  description: >
    Forward bulging (ectasia) of the central/paracentral cornea into the
    characteristic cone, producing progressive steepening. This is the defining
    structural lesion of keratoconus and the substrate for its optical
    consequences and for acute hydrops.
  locations:
  - preferred_term: cornea
    term:
      id: UBERON:0000964
      label: cornea
  downstream:
  - target: Irregular Astigmatism and Optical Degradation
    description: >
      An irregular conical surface refracts light irregularly.
    causal_link_type: DIRECT
  - target: Descemet Membrane Rupture
    description: >
      Progressive ectatic stretching predisposes to a break in Descemet
      membrane.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  evidence:
  - reference: PMID:34991971
    reference_title: "Keratoconus: An updated review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Progressive stromal thinning, rupture of the anterior limiting membrane,
      and subsequent ectasia of the central/paracentral cornea are the most
      commonly observed histopathological findings.
    explanation: >-
      Places central/paracentral ectasia downstream of the stromal-thinning
      lesion.
- name: Irregular Astigmatism and Optical Degradation
  biological_scale: ORGANISM
  description: >
    The irregular conical corneal surface produces irregular astigmatism and
    higher-order aberration, which spectacles correct poorly and which
    manifests clinically as progressively blurred, distorted vision.
  notes: >-
    No downstream edge to "Corneal Stromal Scarring" is asserted. Irregular
    astigmatism and stromal scarring are two independent optical consequences
    of the same ectatic lesion that jointly drive the keratoplasty indication;
    the co-occurrence is not a causal relation, and the evidenced route to
    scarring is advanced ectasia via Descemet membrane rupture.
  evidence:
  - reference: PMID:34991971
    reference_title: "Keratoconus: An updated review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Keratoconus is a bilateral and asymmetric disease which results in
      progressive thinning and steeping of the cornea leading to irregular
      astigmatism and decreased visual acuity.
    explanation: >-
      States the causal chain from corneal thinning/steepening to irregular
      astigmatism and reduced visual acuity.
- name: Descemet Membrane Rupture
  biological_scale: TISSUE
  description: >
    A break in Descemet membrane, the posterior basement membrane of the
    cornea. This is the initiating lesion of acute corneal hydrops: it breaches
    the barrier that normally keeps aqueous humour out of the stroma.
  locations:
  - preferred_term: Descemet's membrane
    term:
      id: UBERON:0004367
      label: Descemet's membrane
  downstream:
  - target: Stromal Imbibition and Acute Corneal Oedema
    description: >
      Loss of the Descemet barrier allows aqueous humour to enter the corneal
      stroma and epithelium.
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:24491416
    reference_title: "Acute corneal hydrops in keratoconus - new perspectives."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Acute corneal hydrops is an incompletely understood complication of
      keratoconus, characterized by marked corneal edema caused by a break in
      Descemet membrane, allowing aqueous to enter the corneal stroma and
      epithelium.
    explanation: >-
      Identifies the Descemet-membrane break as the lesion that causes the
      oedema, establishing it as the upstream event.
- name: Stromal Imbibition and Acute Corneal Oedema
  biological_scale: TISSUE
  description: >
    Aqueous humour entering the stroma and epithelium through the Descemet
    break produces the marked corneal oedema that constitutes clinical acute
    corneal hydrops. It is usually self-limiting, with the oedema resolving
    over about three months.
  locations:
  - preferred_term: corneal stroma
    term:
      id: UBERON:0001777
      label: substantia propria of cornea
  downstream:
  - target: Corneal Stromal Scarring
    description: >
      Resolution of the oedema characteristically leaves a vision-impairing
      scar.
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:24491416
    reference_title: "Acute corneal hydrops in keratoconus - new perspectives."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Acute corneal hydrops is an incompletely understood complication of
      keratoconus, characterized by marked corneal edema caused by a break in
      Descemet membrane, allowing aqueous to enter the corneal stroma and
      epithelium.
    explanation: >-
      Identifies the marked corneal oedema from stromal and epithelial aqueous
      imbibition as the consequence of the Descemet break.
  - reference: PMID:24491416
    reference_title: "Acute corneal hydrops in keratoconus - new perspectives."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Although usually self-limiting, with clinical signs of edema typically
      resolving after 3 months, it often leaves a vision-impairing scar,
      necessitating and expediting the need for corneal transplantation.
    explanation: >-
      Establishes the self-limiting course of the oedema and its progression to
      a vision-impairing scar.
- name: Corneal Stromal Scarring
  biological_scale: TISSUE
  description: >
    Permanent stromal scarring - most characteristically as the sequel of
    resolved acute hydrops - causes irreversible visual impairment and is the
    common final indication for corneal transplantation.
  locations:
  - preferred_term: corneal stroma
    term:
      id: UBERON:0001777
      label: substantia propria of cornea
  evidence:
  - reference: PMID:24491416
    reference_title: "Acute corneal hydrops in keratoconus - new perspectives."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Although usually self-limiting, with clinical signs of edema typically
      resolving after 3 months, it often leaves a vision-impairing scar,
      necessitating and expediting the need for corneal transplantation.
    explanation: >-
      Establishes post-hydrops scarring as the link between the acute event and
      the need for keratoplasty.
phenotypes:
- name: Keratoconus
  category: Eye
  description: >
    The defining phenotype: bilateral, typically asymmetric conical ectasia of
    the cornea with progressive thinning and steepening. Corresponds to the
    "Corneal Ectasia and Conical Protrusion" pathophysiology node.
  frequency: OBLIGATE
  diagnostic: true
  phenotype_term:
    preferred_term: Keratoconus
    term:
      id: HP:0000563
      label: Keratoconus
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:34991971
    reference_title: "Keratoconus: An updated review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Keratoconus is a bilateral and asymmetric disease which results in
      progressive thinning and steeping of the cornea leading to irregular
      astigmatism and decreased visual acuity.
    explanation: >-
      Describes the bilateral, asymmetric, progressive corneal thinning and
      steepening that constitutes the defining phenotype.
- name: Irregular Astigmatism
  category: Eye
  description: >
    Irregular astigmatism arising from the conical, optically irregular corneal
    surface; poorly correctable with spectacles. Corresponds to the "Irregular
    Astigmatism and Optical Degradation" pathophysiology node.
  phenotype_term:
    preferred_term: Irregular astigmatism
    term:
      id: HP:0031792
      label: Irregular astigmatism
  notes: >-
    No frequency band is assigned: the cited review establishes irregular
    astigmatism as the characteristic optical consequence but does not
    quantify the proportion of patients affected.
  evidence:
  - reference: PMID:34991971
    reference_title: "Keratoconus: An updated review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Keratoconus is a bilateral and asymmetric disease which results in
      progressive thinning and steeping of the cornea leading to irregular
      astigmatism and decreased visual acuity.
    explanation: >-
      Directly attributes irregular astigmatism to the corneal thinning and
      steepening of keratoconus.
- name: Reduced Visual Acuity
  category: Eye
  description: >
    Progressive blurring and decrease of visual acuity, the dominant symptomatic
    burden of keratoconus and the reason it is a leading cause of keratoplasty
    in young adults.
  phenotype_term:
    preferred_term: Reduced visual acuity
    term:
      id: HP:0007663
      label: Reduced visual acuity
    clinical_course: PROGRESSIVE
  notes: >-
    No frequency band is assigned; the cited sources establish visual loss as a
    characteristic consequence without a quantified proportion.
  evidence:
  - reference: PMID:24357835
    reference_title: "The pathogenesis of keratoconus."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Keratoconus (KC) is a common degenerative condition that frequently
      results in visual loss with an onset typically in early adulthood.
    explanation: >-
      States that keratoconus frequently results in visual loss with
      early-adulthood onset.
- name: Corneal Scarring
  category: Eye
  description: >
    Vision-impairing corneal stromal scarring, characteristically following
    resolution of acute corneal hydrops, and a principal indication for
    keratoplasty. Corresponds to the "Corneal Stromal Scarring" pathophysiology
    node.
  phenotype_term:
    preferred_term: Corneal scarring
    term:
      id: HP:0000559
      label: Corneal scarring
  evidence:
  - reference: PMID:24491416
    reference_title: "Acute corneal hydrops in keratoconus - new perspectives."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Although usually self-limiting, with clinical signs of edema typically
      resolving after 3 months, it often leaves a vision-impairing scar,
      necessitating and expediting the need for corneal transplantation.
    explanation: >-
      Documents vision-impairing scarring as the usual residuum of acute
      hydrops in keratoconus.
- name: Corneal Stromal Oedema
  category: Eye
  description: >
    Marked oedema of the corneal stroma and epithelium during acute corneal
    hydrops, when aqueous humour enters the stroma through a break in Descemet
    membrane. Typically resolves over about three months. Corresponds to the
    "Stromal Imbibition and Acute Corneal Oedema" pathophysiology node.
  phenotype_term:
    preferred_term: Corneal stromal oedema
    term:
      id: HP:0012040
      label: Corneal stromal edema
    temporality: ACUTE
  notes: >-
    No frequency band is assigned: acute hydrops is a recognised complication
    of keratoconus but the cited source does not quantify what proportion of
    patients experience it.
  evidence:
  - reference: PMID:24491416
    reference_title: "Acute corneal hydrops in keratoconus - new perspectives."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Acute corneal hydrops is an incompletely understood complication of
      keratoconus, characterized by marked corneal edema caused by a break in
      Descemet membrane, allowing aqueous to enter the corneal stroma and
      epithelium.
    explanation: >-
      Names marked corneal oedema of the stroma and epithelium as the defining
      clinical finding of acute hydrops in keratoconus.
- name: Corneal Iron Line (Fleischer Ring)
  category: Eye
  description: >
    Arcuate or annular deposition of iron in the corneal epithelial basement
    membrane at the base of the cone - the Fleischer ring - one of the classic
    slit-lamp signs of keratoconus.
  phenotype_term:
    preferred_term: Fleischer ring
    term:
      id: HP:6001232
      label: Corneal iron line
  notes: >-
    preferred_term uses the clinical eponym; the HPO term is the more general
    "Corneal iron line", whose own definition names keratoconus as a typical
    setting. No frequency band is assigned - the cited source lists it as a
    classic feature without quantifying it.
  evidence:
  - reference: PMID:9493273
    reference_title: "Keratoconus."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Classic histopathologic features include stromal thinning, iron
      deposition in the epithelial basement membrane, and breaks in Bowman's
      layer.
    explanation: >-
      Documents epithelial basement-membrane iron deposition as a classic
      feature of keratoconus.
- name: Vogt striae
  category: Eye
  description: >
    Fine vertical stress lines in the posterior cornea caused by compression of
    Descemet membrane; a characteristic slit-lamp sign of clinically manifest
    keratoconus.
  notes: >-
    No phenotype term is bound because the current local HPO cache has no
    specific Vogt-striae term. No frequency band is asserted by this source.
  evidence:
  - reference: PMID:20537579
    reference_title: "Keratoconus: a review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Vogt's striaes, which are fine vertical lines produced by Descemet's membrane compression, is another characteristic sign."
    explanation: >-
      The review directly defines Vogt striae and identifies them as a
      characteristic keratoconus sign.
histopathology:
- name: Stromal Thinning
  description: >
    Reduction in corneal stromal thickness, the most consistently reported
    microscopic finding in keratoconus and the tissue-level correlate of the
    "Progressive Stromal Thinning" pathophysiology node.
  notes: >-
    No finding_term is bound: the NCIT Histopathology Result branch has no
    term for corneal stromal thinning, and per repository convention a missing
    term is preferable to omitting a real finding or forcing a poor-fit term.
  evidence:
  - reference: PMID:34991971
    reference_title: "Keratoconus: An updated review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Progressive stromal thinning, rupture of the anterior limiting membrane,
      and subsequent ectasia of the central/paracentral cornea are the most
      commonly observed histopathological findings.
    explanation: >-
      Explicitly names stromal thinning among the most commonly observed
      histopathological findings.
- name: Breaks in Bowman's Layer
  description: >
    Ruptures of the anterior limiting membrane (Bowman's layer), reported as a
    classic histopathologic feature and the tissue-level correlate of the
    "Anterior Limiting Membrane Rupture" pathophysiology node.
  notes: >-
    No finding_term is bound; NCIT has no corresponding corneal morphologic
    finding term.
  evidence:
  - reference: PMID:9493273
    reference_title: "Keratoconus."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Classic histopathologic features include stromal thinning, iron
      deposition in the epithelial basement membrane, and breaks in Bowman's
      layer.
    explanation: >-
      Names breaks in Bowman's layer among the classic histopathologic
      features of keratoconus.
- name: Iron Deposition in the Epithelial Basement Membrane
  description: >
    Deposition of iron in the corneal epithelial basement membrane, the
    microscopic basis of the clinically visible Fleischer ring.
  notes: >-
    No finding_term is bound; NCIT has no corneal iron-deposition morphologic
    finding term. The clinical counterpart is curated as the "Corneal Iron
    Line (Fleischer Ring)" phenotype.
  evidence:
  - reference: PMID:9493273
    reference_title: "Keratoconus."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Classic histopathologic features include stromal thinning, iron
      deposition in the epithelial basement membrane, and breaks in Bowman's
      layer.
    explanation: >-
      Names epithelial basement-membrane iron deposition among the classic
      histopathologic features.
genetic:
- name: Polygenic susceptibility architecture
  relationship_type: SUSCEPTIBILITY
  notes: >-
    No single gene entry is given for the GWAS signal itself: 36 loci were
    identified and no individual locus is causative on its own. Per-gene
    entries below record the most frequently investigated candidate loci, whose
    individual causal validity is not established.
  evidence:
  - reference: PMID:33649486
    reference_title: "A multi-ethnic genome-wide association study implicates collagen matrix integrity and cell differentiation pathways in keratoconus."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here we report the first large scale genome-wide association study of
      keratoconus including 4,669 cases and 116,547 controls.
    explanation: >-
      Establishes the scale of the GWAS underpinning the polygenic
      susceptibility model.
  - reference: PMID:39535071
    reference_title: "Developing and validating a comprehensive polygenic risk score to enhance keratoconus risk prediction."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The PRS models demonstrated significant predictive capabilities in EstBB,
      with the SBayesRC model achieving the highest OR of 2.28 per standard
      deviation increase in PRS
    explanation: >-
      A polygenic risk score built from the GWAS predicts keratoconus liability
      in an independent biobank, which is the operational demonstration that the
      polygenic architecture recorded here carries real predictive signal rather
      than being a statistical artefact of the discovery cohort.
  - reference: PMID:39535071
    reference_title: "Developing and validating a comprehensive polygenic risk score to enhance keratoconus risk prediction."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In UKB, we found that adding the best-performing PRS to a model containing
      corneal measurements increased the AUC from 0.84 to 0.88 (P = 0.012 for
      difference)
    explanation: >-
      Shows the polygenic signal adds information beyond corneal measurements,
      relevant to the potential for genetic risk stratification raised in the
      primary-pathomechanism knowledge gap.
- name: COL5A1
  gene_term:
    preferred_term: COL5A1
    term:
      id: hgnc:2209
      label: COL5A1
  relationship_type: SUSCEPTIBILITY
  notes: >-
    COL5A1 encodes a fibrillar collagen of the corneal stroma. It reaches
    genome-wide significance in the multi-ethnic GWAS (rs3118518) and is one of
    the six loci previously associated with keratoconus that the GWAS
    recovered; candidate-gene work had separately prioritised rs1536482 and
    rs7044529 for replication genotyping.
  evidence:
  - reference: PMID:33649486
    reference_title: "A multi-ethnic genome-wide association study implicates collagen matrix integrity and cell differentiation pathways in keratoconus."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      9q34.3 9 137412655..137566891 rs3118518 A G 0.270 0.024 1.83E −28
      COL5A1,RXRA
    explanation: >-
      The final trans-ethnic meta-analysis table gives the genome-wide
      significant COL5A1 association (rs3118518).
  - reference: PMID:30816092
    reference_title: "[Search for genetic markers for precise diagnostics of keratoconus]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the following candidate variants were selected for genotyping in the
      Russian population of patients with keratoconus: rs1536482 and rs7044529
      in the COL5A1 gene
    explanation: >-
      A systematic review of keratoconus markers selects COL5A1 variants as
      prioritised candidates after replication assessment.
- name: HGF
  gene_term:
    preferred_term: HGF
    term:
      id: hgnc:4893
      label: HGF
  relationship_type: SUSCEPTIBILITY
  notes: >-
    HGF variants rs5745752 and rs2286194 were among the candidates prioritised
    on the basis of replication evidence.
  evidence:
  - reference: PMID:30816092
    reference_title: "[Search for genetic markers for precise diagnostics of keratoconus]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "rs5745752 and rs2286194 in the HGF gene"
    explanation: >-
      Identifies the prioritised HGF candidate variants for keratoconus
      genotyping.
- name: VSX1
  gene_term:
    preferred_term: VSX1
    term:
      id: hgnc:12723
      label: VSX1
  relationship_type: DISPUTED
  notes: >-
    VSX1 is the most historically cited candidate gene for keratoconus but its
    causal role is contested; it is listed here as an analysed marker whose
    validity is unsettled amid broad genetic heterogeneity.
  evidence:
  - reference: PMID:30816092
    reference_title: "[Search for genetic markers for precise diagnostics of keratoconus]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The analysis included markers in VSX1, SOD1, ZEB1, LOX, CAST, DOCK9,
      TGFBI, HGF, MAP3K19, KCND3, COL4A3, COL4A4, COL5A1, FNDC3B, FOXO1,
      BANP-ZNF469, MPDZ-NF1B, WNT10A genes.
    explanation: >-
      VSX1 appears among the analysed candidate markers but was not among the
      variants prioritised for replication genotyping, consistent with disputed
      status.
  - reference: PMID:30816092
    reference_title: "[Search for genetic markers for precise diagnostics of keratoconus]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The studies of causal mutations indicate the genetic heterogeneity of
      keratoconus, which complicates the development of a diagnostic panel.
    explanation: >-
      Supports the framing that no single candidate gene, VSX1 included, has
      established causal primacy.
- name: LOX
  gene_term:
    preferred_term: LOX
    term:
      id: hgnc:6664
      label: LOX
  relationship_type: SUSCEPTIBILITY
  notes: >-
    LOX (lysyl oxidase) catalyses the collagen and elastin cross-linking that
    determines stromal tensile strength - the same chemistry that riboflavin/UV-A
    corneal cross-linking supplies therapeutically - making it both a
    mechanistically attractive and a statistically supported locus. Unlike VSX1
    (typed DISPUTED here), LOX reaches genome-wide significance in the
    multi-ethnic GWAS with an accompanying eQTL effect on its own transcription,
    so the SUSCEPTIBILITY typing does not rest on the shared
    "analysed markers" sentence of the candidate-marker review.
  evidence:
  - reference: PMID:33649486
    reference_title: "A multi-ethnic genome-wide association study implicates collagen matrix integrity and cell differentiation pathways in keratoconus."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      5q23.2 5 121269498..121426675 rs840464 T G 0.233 0.025 1.72E −20
      SRFBP1,LOX
    explanation: >-
      The final trans-ethnic meta-analysis table gives the genome-wide
      significant LOX-locus association (rs840464), an actual association
      result rather than mere inclusion among analysed markers.
  - reference: PMID:33649486
    reference_title: "A multi-ethnic genome-wide association study implicates collagen matrix integrity and cell differentiation pathways in keratoconus."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      LOX encodes lysyl oxidase, an enzyme that initiates the cross-linking of
      collagens and elastin
    explanation: >-
      Supplies the mechanistic rationale linking the LOX locus to the stromal
      collagen cross-linking that determines corneal tensile strength.
- name: COL12A1
  gene_term:
    preferred_term: COL12A1
    term:
      id: hgnc:2188
      label: COL12A1
  relationship_type: SUSCEPTIBILITY
  notes: >-
    COL12A1 carries the strongest coding signal in the multi-ethnic GWAS: a
    missense variant (rs35523808, p.Glu2160Val) predicted deleterious. Collagen
    XII localises to Bowman's layer and the interfibrillar stromal matrix,
    connecting the locus directly to the "Anterior Limiting Membrane Rupture"
    and "Progressive Stromal Thinning" pathophysiology nodes.
  evidence:
  - reference: PMID:33649486
    reference_title: "A multi-ethnic genome-wide association study implicates collagen matrix integrity and cell differentiation pathways in keratoconus."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      a missense and potentially deleterious variant within COL12A1
    explanation: >-
      Identifies a genome-wide significant, potentially deleterious COL12A1
      missense variant as a keratoconus association.
- name: FNDC3B
  gene_term:
    preferred_term: FNDC3B
    term:
      id: hgnc:24670
      label: FNDC3B
  relationship_type: SUSCEPTIBILITY
  notes: >-
    FNDC3B (rs4894414) is one of the six loci previously associated with
    keratoconus that the multi-ethnic GWAS recovered at genome-wide
    significance. It is transcriptionally downstream of KLF5, the corneal
    epithelial identity factor also implicated at this GWAS, placing it in the
    cell-differentiation arm of the disease mechanism rather than the
    collagen-matrix arm.
  evidence:
  - reference: PMID:33649486
    reference_title: "A multi-ethnic genome-wide association study implicates collagen matrix integrity and cell differentiation pathways in keratoconus."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      suppressed levels of FNDC3B, another gene associated with keratoconus in
      our study
    explanation: >-
      Names FNDC3B as a keratoconus-associated gene and links it to KLF5-driven
      corneal epithelial differentiation.
- name: ZNF469
  gene_term:
    preferred_term: ZNF469
    term:
      id: hgnc:23216
      label: ZNF469
  relationship_type: SUSCEPTIBILITY
  notes: >-
    ZNF469 is the best-known corneal-thickness locus and is associated with
    keratoconus in a direction that dissociates the two traits: the risk alleles
    raise central corneal thickness yet increase keratoconus risk. The GWAS
    authors use exactly this divergence to argue that mechanisms of corneal
    fragility independent of corneal thickness contribute to keratoconus.
  evidence:
  - reference: PMID:33649486
    reference_title: "A multi-ethnic genome-wide association study implicates collagen matrix integrity and cell differentiation pathways in keratoconus."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      alleles upstream of the ZNF469 locus that is associated with a higher CCT
      but an increased risk for keratoconus
    explanation: >-
      Documents the ZNF469 association and its counterintuitive direction
      relative to central corneal thickness.
  - reference: PMID:33649486
    reference_title: "A multi-ethnic genome-wide association study implicates collagen matrix integrity and cell differentiation pathways in keratoconus."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This supports the view that other mechanisms of loss of corneal integrity
      and corneal fragility, independent of corneal thickness, contribute to
      the pathogenesis of keratoconus.
    explanation: >-
      The authors' own interpretation that thickness-independent corneal
      fragility mechanisms operate, which is why ZNF469 is typed as a
      susceptibility rather than a thickness-proxy locus.
- name: ALDH3A1
  gene_term:
    preferred_term: ALDH3A1
    term:
      id: hgnc:405
      label: ALDH3A1
  relationship_type: SUSCEPTIBILITY
  notes: >-
    ALDH3A1 (rs4646785) encodes a corneal crystallin that is a major structural
    and protective component of the corneal stroma and epithelium, and is
    upregulated in keratoconus corneas. The associated SNP is also a
    significant eQTL for the gene, giving a candidate regulatory mechanism.
  evidence:
  - reference: PMID:33649486
    reference_title: "A multi-ethnic genome-wide association study implicates collagen matrix integrity and cell differentiation pathways in keratoconus."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      ALDH3A1 encodes a corneal crystallin, a major component of the corneal
      stroma and epithelium that is upregulated in keratoconus corneas compared
      to controls
    explanation: >-
      Links the ALDH3A1 association to a corneal-stroma protein demonstrably
      dysregulated in keratoconus tissue.
- name: ITGA2
  gene_term:
    preferred_term: ITGA2
    term:
      id: hgnc:6137
      label: ITGA2
  relationship_type: SUSCEPTIBILITY
  notes: >-
    ITGA2 (rs12515400) encodes the alpha-2 subunit of the integrin alpha-2/beta-1
    collagen receptor, which promotes type I collagen polymerisation - a
    plausible route from a common variant to the collagen-matrix integrity
    defect the GWAS implicates.
  evidence:
  - reference: PMID:33649486
    reference_title: "A multi-ethnic genome-wide association study implicates collagen matrix integrity and cell differentiation pathways in keratoconus."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The protein encoded by this gene participates in complexes of integrin
      α2β1, which are collagen receptors
    explanation: >-
      Gives the collagen-receptor function of the ITGA2 product at the
      associated locus.
inheritance:
- name: Polygenic inheritance
  description: >
    Common keratoconus is a complex, polygenic trait: 36 GWAS loci with common
    variants explaining 12.5% of the genetic variance, with a strong familial
    aggregation signal (odds ratio 6.42 for a positive family history) but no
    single Mendelian locus.
  inheritance_term:
    preferred_term: Polygenic inheritance
    term:
      id: HP:0010982
      label: Polygenic inheritance
  evidence:
  - reference: PMID:33649486
    reference_title: "A multi-ethnic genome-wide association study implicates collagen matrix integrity and cell differentiation pathways in keratoconus."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The common variants associated with keratoconus explain 12.5% of the genetic variance"
    explanation: >-
      Quantifies a polygenic common-variant contribution, supporting polygenic
      rather than Mendelian inheritance.
  - reference: PMID:9493273
    reference_title: "Keratoconus."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinical studies provide strong indications of a major role for genes in its etiology."
    explanation: >-
      Corroborates a substantial genetic contribution to keratoconus aetiology.
environmental:
- name: Eye rubbing
  influences_mechanisms:
  - target: Chronic Mechanical Eye Rubbing
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: >-
      The entry models the exposure itself as a node, so this link is an
      identity rather than a causal step: habitual rubbing and chronic
      mechanical loading of the cornea are the same thing. Rubbing carries the
      largest modifiable effect in this disease, which is why counselling to
      stop is the first intervention.
    evidence:
    - reference: PMID:31498247
      reference_title: "The Prevalence and Risk Factors for Keratoconus: A Systematic Review and Meta-Analysis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "eye rubbing, family history of keratoconus, allergy, asthma, and eczema were the most important risk factors for keratoconus according to the available evidence"
      explanation: >-
        Names eye rubbing first among the most important risk factors for
        keratoconus, the mechanical exposure this node represents.
  description: >
    Habitual mechanical eye rubbing is the best-replicated modifiable
    environmental risk factor for keratoconus (OR 3.09) and is a target of
    patient counselling.
  effect: Increases risk of developing and of progressing keratoconus
  evidence:
  - reference: PMID:31498247
    reference_title: "The Prevalence and Risk Factors for Keratoconus: A Systematic Review and Meta-Analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      eye rubbing, family history of keratoconus, allergy, asthma, and eczema
      were the most important risk factors for keratoconus according to the
      available evidence
    explanation: >-
      Identifies eye rubbing as among the most important risk factors in the
      most comprehensive meta-analysis to date.
- name: Atopic diathesis (allergy, asthma, eczema)
  influences_mechanisms:
  - target: Chronic Mechanical Eye Rubbing
    environmental_effect: PREDISPOSES
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Atopy acts largely through itch: allergic conjunctivitis provokes the
      rubbing that damages the cornea. Targeting the rubbing node rather than
      a corneal node records that indirection, which is why treating the
      allergy is a way of treating the keratoconus risk.
    evidence:
    - reference: PMID:31498247
      reference_title: "The Prevalence and Risk Factors for Keratoconus: A Systematic Review and Meta-Analysis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The odds ratio of eye rubbing, family history of keratoconus, allergy, asthma, and eczema was 3.09 (95% CI: 2.17-4.00), 6.42 (95% CI: 2.59-10.24), 1.42 (95% CI: 1.06-1.79), 1.94 (95% CI: 1.30-2.58), and 2.95 (95% CI: 1.30-4.59), respectively."
      explanation: >-
        Gives odds ratios for allergy, asthma and eczema alongside eye
        rubbing, the atopic conditions that provoke rubbing behaviour.
  description: >
    Atopic disease raises keratoconus risk (allergy OR 1.42, asthma OR 1.94,
    eczema OR 2.95), plausibly at least partly through the itch-driven eye
    rubbing it provokes and through ocular surface inflammation.
  effect: Increases risk of keratoconus
  evidence:
  - reference: PMID:31498247
    reference_title: "The Prevalence and Risk Factors for Keratoconus: A Systematic Review and Meta-Analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The odds ratio of eye rubbing, family history of keratoconus, allergy,
      asthma, and eczema was 3.09 (95% CI: 2.17-4.00), 6.42 (95% CI:
      2.59-10.24), 1.42 (95% CI: 1.06-1.79), 1.94 (95% CI: 1.30-2.58), and 2.95
      (95% CI: 1.30-4.59), respectively.
    explanation: >-
      Quantifies the atopy-associated odds ratios for keratoconus.
- name: Ultraviolet light exposure
  exposure_term:
    preferred_term: exposure to ultraviolet radiation
    term:
      id: ECTO:0000006
      label: exposure to ultraviolet radiation
  influences_mechanisms:
  - target: Corneal Oxidative Stress
    environmental_effect: PREDISPOSES
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Ultraviolet exposure is associated with progression and plausibly acts
      through oxidative damage to the stroma, but the direction is
      complicated: ultraviolet A with riboflavin is the basis of corneal
      cross-linking, the standard treatment that halts progression. Dose and
      cofactors decide which effect dominates.
    evidence:
    - reference: PMID:39448666
      reference_title: "Keratoconus."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Environmental factors, such as eye rubbing, UV light exposure and contact lens wearing, are associated with disease progression."
      explanation: >-
        Names ultraviolet light exposure among the environmental factors
        associated with disease progression, an association without an
        identified mediating step.
  description: >
    Ultraviolet light exposure is named in the authoritative disease primer,
    alongside eye rubbing and contact lens wear, as an environmental factor
    associated with keratoconus progression. The primer states the association
    with progression; it does not quantify an effect size, and no causal
    mechanism is asserted here.
  effect: Associated with progression of keratoconus
  evidence:
  - reference: PMID:39448666
    reference_title: "Keratoconus."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Environmental factors, such as eye rubbing, UV light exposure and contact
      lens wearing, are associated with disease progression.
    explanation: >-
      The Nature Reviews Disease Primers article names UV light exposure as an
      environmental factor associated with disease progression.
- name: Contact lens wear
  influences_mechanisms:
  - target: Chronic Mechanical Eye Rubbing
    environmental_effect: PREDISPOSES
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Lens wear reaches this node through the same named intermediate as atopy,
      irritation provoking rubbing, so it carries the same link type. What is
      uncertain here is not the intermediate but the direction: lenses are also
      the commonest treatment for the refractive error keratoconus produces, so
      wearers are enriched for existing disease. That confounding is why the
      effect is graded PREDISPOSES rather than anything stronger.
    evidence:
    - reference: PMID:39448666
      reference_title: "Keratoconus."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Environmental factors, such as eye rubbing, UV light exposure and contact lens wearing, are associated with disease progression."
      explanation: >-
        Names contact lens wearing among the environmental factors associated
        with disease progression, without separating cause from consequence of
        the disease.
  description: >
    Contact lens wear is named in the disease primer as an environmental factor
    associated with keratoconus progression. Note the confounding: rigid and
    scleral lenses are also the mainstay of visual rehabilitation in this entry's
    treatment section, so lens wear is both an exposure and a consequence of
    established disease, and the primer does not separate the two.
  effect: Associated with progression of keratoconus
  evidence:
  - reference: PMID:39448666
    reference_title: "Keratoconus."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Environmental factors, such as eye rubbing, UV light exposure and contact
      lens wearing, are associated with disease progression.
    explanation: >-
      The Nature Reviews Disease Primers article names contact lens wearing as
      an environmental factor associated with disease progression.
prevalence:
- population: Worldwide
  measure_type: POINT_PREVALENCE
  prevalence_class: ABOVE_1_IN_1000
  rate_per_100000: 138.0
  rate_low: 114.0
  rate_high: 162.0
  notes: >-
    Meta-analysis of 29 studies covering 7,158,241 participants from 15
    countries: 1.38 per 1000 (95% CI 1.14-1.62 per 1000), i.e. 138 per 100,000.
  evidence:
  - reference: PMID:31498247
    reference_title: "The Prevalence and Risk Factors for Keratoconus: A Systematic Review and Meta-Analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The prevalence of keratoconus in the whole population was 1.38 per 1000
      population
    explanation: >-
      Provides the pooled worldwide prevalence estimate normalised here to 138
      per 100,000.
- population: Netherlands (nationwide health-insurance database, 4.4 million patients)
  measure_type: POINT_PREVALENCE
  prevalence_class: ABOVE_1_IN_1000
  rate_per_100000: 265.0
  rate_low: 260.0
  rate_high: 270.0
  notes: >-
    Registry-based estimate in the era of modern topographic diagnostics
    (1:375); the authors note this is 5- to 10-fold higher than older
    population-study estimates, so the worldwide meta-analytic figure above and
    this one are not directly comparable.
  evidence:
  - reference: PMID:28039037
    reference_title: "Age-specific Incidence and Prevalence of Keratoconus: A Nationwide Registration Study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the estimated prevalence of keratoconus in the general population was
      1:375 (265 cases per 100 000, 95% CI: 260-270)
    explanation: >-
      Gives the nationwide registry prevalence estimate normalised to 265 per
      100,000.
- population: Netherlands, ages 10-40 years
  measure_type: ANNUAL_INCIDENCE
  rate_per_100000: 13.3
  rate_low: 11.6
  rate_high: 15.2
  notes: >-
    Annual incidence of newly diagnosed keratoconus in the age band in which it
    typically presents (13.3 cases per 100,000, 95% CI 11.6-15.2). No
    prevalence_class is asserted: the Orphanet classes are prevalence bands and
    applying one to an incidence measure would conflate the two.
  evidence:
  - reference: PMID:28039037
    reference_title: "Age-specific Incidence and Prevalence of Keratoconus: A Nationwide Registration Study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The annual incidence of keratoconus was 1:7500 in the relevant age
      category
    explanation: >-
      Provides the age-specific annual incidence used for this record.
- population: Persons with Down syndrome
  measure_type: POINT_PREVALENCE
  prevalence_class: UNKNOWN
  notes: >-
    Keratoconus is markedly over-represented in Down syndrome, but reported
    prevalences range from 0% to 71% across 20 studies of widely varying design
    and quality, so no numeric rate is asserted here. Screening in this group
    should be considered.
  evidence:
  - reference: PMID:33981858
    reference_title: "Prevalence of keratoconus in persons with Down syndrome: a review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The present review showed that the prevalence of keratoconus in persons
      with Down syndrome is higher than in the general population. However,
      estimates from previous studies vary widely.
    explanation: >-
      Supports elevated but imprecisely quantified prevalence in Down syndrome.
progression:
- phase: Onset and progression
  age_range: Second to fourth decade
  notes: >-
    Keratoconus typically develops in the second and third decades and
    progresses until roughly the fourth decade; the mean age at diagnosis in a
    nationwide registry was 28.3 years.
  evidence:
  - reference: PMID:34991971
    reference_title: "Keratoconus: An updated review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Keratoconus normally develops in the second and third decades of life and
      progresses until the fourth decade.
    explanation: Gives the characteristic onset and progression window.
  - reference: PMID:28039037
    reference_title: "Age-specific Incidence and Prevalence of Keratoconus: A Nationwide Registration Study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The mean age at diagnosis was 28.3 years and 60.6% of diagnosed patients were male."
    explanation: >-
      Provides the registry-based mean age at diagnosis and a male
      preponderance among diagnosed patients.
- phase: Documented progression (the cross-linking indication)
  notes: >-
    How "progression" is operationalised is the decision point for offering
    cross-linking, and the literature has no unified criterion. A systematic
    review of 221 articles found anterior-curvature data used in 97.8%, with
    maximum keratometry (Kmax) the single most frequent criterion (85.5%),
    followed by refractive astigmatism and thinnest-point pachymetry;
    progression was assessed over a 6- to 12-month follow-up in 64.7%. Posterior
    corneal data were used in only 8.1% of studies and epithelial data in none,
    so the criteria in common use underexploit available tomography. The Global
    Delphi consensus in the diagnosis section is the corresponding expert
    statement; this record captures what the primary literature actually uses.
  evidence:
  - reference: PMID:39671084
    reference_title: "Definition of Progressive Keratoconus: A Systematic Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the most frequent criterion used was maximum keratometry (Kmax), used in
      85.5% (189/221) of the articles
    explanation: >-
      Identifies Kmax as the dominant operational criterion for progression
      across the reviewed literature.
  - reference: PMID:39671084
    reference_title: "Definition of Progressive Keratoconus: A Systematic Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Progression was assessed between 6- and 12-month follow-up in 64.7%
      (143/221) of the articles.
    explanation: >-
      Gives the follow-up interval over which progression is conventionally
      assessed.
  - reference: PMID:39671084
    reference_title: "Definition of Progressive Keratoconus: A Systematic Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The present study demonstrates the lack of unified criteria to define
      progression of keratoconus and an underutilization of the technology
      described.
    explanation: >-
      Qualifies the record: the criteria above are the most common ones, not an
      agreed standard. Typed PARTIAL because it constrains rather than
      establishes the progression definition.
diagnosis:
- name: Corneal topography
  description: >
    Corneal topography is the primary diagnostic modality. Early/subclinical
    disease is difficult to detect and no single parameter suffices, so
    topography is combined with corneal pachymetry and higher-order aberration
    measurement.
  evidence:
  - reference: PMID:34991971
    reference_title: "Keratoconus: An updated review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Corneal topography is the primary diagnostic tool for keratoconus detection."
    explanation: Establishes corneal topography as the primary diagnostic tool.
  - reference: PMID:34991971
    reference_title: "Keratoconus: An updated review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In incipient cases, however, the use of a single parameter to diagnose
      keratoconus is insufficient, and in addition to corneal topography,
      corneal pachymetry and higher order aberration data are now commonly used.
    explanation: >-
      Supports the multi-parameter approach required for incipient disease.
- name: Global Delphi consensus criteria for keratoconus and ectatic disease
  description: >
    There is no single validated gold-standard test. The reference framework
    for definition, diagnosis, staging and staged management is the Global
    Delphi consensus. Edition 2 (2026) is the current statement - 128
    ophthalmologists from 6 continents, 4 questionnaire rounds plus a
    face-to-face meeting, two-thirds agreement threshold - superseding the 2015
    first edition (36 panelists, 3 rounds), which remains the consensus
    underlying most of the intervening literature. Both are consensus
    instruments rather than prospectively validated diagnostic algorithms, and
    each panel was convened precisely because controversies persist.
  evidence:
  - reference: PMID:42228627
    reference_title: "Global Consensus on Keratoconus and Ectatic Diseases-Edition 2."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      A significant consensus was reached on topics such as definitions,
      diagnostic and progression criteria, and management strategies for
      keratoconus and other ectatic corneal disorders.
    explanation: >-
      The current (Edition 2) consensus is the source of the field's
      definitions, diagnostic criteria and progression criteria.
  - reference: PMID:42228627
    reference_title: "Global Consensus on Keratoconus and Ectatic Diseases-Edition 2."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      This updated Global Consensus provides revised definitions, expert
      statements, and recommendations for diagnosing and managing keratoconus
      and other ectatic corneal diseases.
    explanation: >-
      Confirms that Edition 2 revises rather than restates the 2015
      definitions, which is why it is cited here as the current framework.
  - reference: PMID:25738235
    reference_title: "Global consensus on keratoconus and ectatic diseases."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Numerous agreements were generated in definitions, methods of diagnosing,
      and management of keratoconus and other ectatic diseases.
    explanation: >-
      The 2015 first edition, retained because it is the consensus underlying
      most of the diagnostic and management literature cited elsewhere here.
  - reference: PMID:25738235
    reference_title: "Global consensus on keratoconus and ectatic diseases."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Despite extensive knowledge regarding the diagnosis and management of
      keratoconus and ectatic corneal diseases, many controversies still exist.
    explanation: >-
      Qualifies the consensus: it codifies expert agreement over persisting
      controversy rather than resolving diagnosis empirically.
treatments:
- name: Riboflavin/UV-A Corneal Collagen Cross-Linking
  description: >
    Corneal collagen cross-linking (CXL) is the established disease-modifying
    treatment for progressive keratoconus. UV-A photo-activation of riboflavin
    drives photochemistry that forms covalent cross-links within stromal
    proteins, reorganising the stroma ultrastructurally and stiffening it, which
    arrests ectatic progression. In the randomised US multicentre trial maximum
    keratometry fell by 1.6 D at one year while controls progressed. Protocols
    have expanded from the original epithelium-off technique to transepithelial
    approaches.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: corneal collagen cross-linking (riboflavin/UV-A phototherapy)
    term:
      id: NCIT:C15301
      label: Phototherapy
    therapeutic_agent:
    - preferred_term: riboflavin
      term:
        id: CHEBI:17015
        label: riboflavin
  target_mechanisms:
  - target: Loss of Corneal Biomechanical Rigidity
    treatment_effect: RESTORES
    description: >
      Photochemically induced covalent cross-links within stromal proteins
      stiffen the cornea, directly counteracting the loss of biomechanical
      rigidity.
  target_phenotypes:
  - preferred_term: Keratoconus
    term:
      id: HP:0000563
      label: Keratoconus
  evidence:
  - reference: PMID:12719068
    reference_title: "Riboflavin/ultraviolet-a-induced collagen crosslinking for the treatment of keratoconus."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In all treated eyes, the progression of keratoconus was at least stopped."
    explanation: >-
      The original clinical pilot study of riboflavin/UVA cross-linking reports
      arrest of progression in all treated eyes.
  - reference: PMID:28495149
    reference_title: "United States Multicenter Clinical Trial of Corneal Collagen Crosslinking for Keratoconus Treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In the CXL treatment group, the maximum keratometry value decreased by 1.6
      diopters (D) from baseline to 1 year, whereas keratoconus continued to
      progress in the control group.
    explanation: >-
      A prospective randomised sham-controlled multicentre trial demonstrating
      efficacy against progression.
  - reference: PMID:42430076
    reference_title: "The Science and Clinical Evolution of Corneal Cross-Linking: Mechanism of Action, Ultra-Structural Changes, Clinical Indications, and Emerging Treatment Strategies."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      CXL acts through UV-A photo-activated riboflavin-driven photochemistry
      that induces covalent cross-links within stromal proteins.
    explanation: >-
      States the molecular mechanism of action linking the treatment to the
      biomechanical-rigidity node it targets.
- name: Rigid and Scleral Contact Lenses
  description: >
    Optical rehabilitation with rigid gas-permeable or scleral contact lenses
    masks the irregular corneal surface with a regular refracting interface and
    remains the mainstay of visual correction in moderate disease. Mild cases
    may be managed with spectacles alone; failure of scleral lenses is a trigger
    for surgical management.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: therapeutic contact lens usage
  target_phenotypes:
  - preferred_term: Irregular astigmatism
    term:
      id: HP:0031792
      label: Irregular astigmatism
  - preferred_term: Reduced visual acuity
    term:
      id: HP:0007663
      label: Reduced visual acuity
  notes: >-
    Symptomatic/optical management: it corrects the refractive consequence but
    does not modify the ectatic process, so no target_mechanisms link is
    asserted.
  evidence:
  - reference: PMID:34991971
    reference_title: "Keratoconus: An updated review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mild cases are typically treated with spectacles, moderate cases with
      contact lenses, while severe cases that cannot be managed with scleral
      contact lenses may require corneal surgery.
    explanation: >-
      Describes the stepwise optical management and the point at which surgery
      becomes necessary.
  - reference: PMID:9493273
    reference_title: "Keratoconus."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Contact lenses are the most common treatment modality."
    explanation: Corroborates contact lenses as the commonest treatment modality.
- name: Corneal Transplantation (Keratoplasty)
  description: >
    Corneal transplantation is reserved for advanced disease, contact-lens
    failure, or scarring (notably post-hydrops scarring). Keratoconus is the
    single most common indication for keratoplasty in the developed world.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: corneal transplantation
    term:
      id: NCIT:C210959
      label: Corneal Transplantation
  target_mechanisms:
  - target: Corneal Stromal Scarring
    treatment_effect: BYPASSES
    description: >
      Replacing the scarred, ectatic host cornea with donor tissue bypasses the
      irreversible structural lesion rather than modifying the disease process.
  target_phenotypes:
  - preferred_term: Corneal scarring
    term:
      id: HP:0000559
      label: Corneal scarring
  evidence:
  - reference: PMID:9493273
    reference_title: "Keratoconus."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      When contact lenses fail, corneal transplant is the best and most
      successful surgical option.
    explanation: >-
      Positions keratoplasty as the surgical option after contact-lens failure.
  - reference: PMID:24357835
    reference_title: "The pathogenesis of keratoconus."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It is the single most common reason for keratoplasty in the developed world."
    explanation: >-
      Quantifies the clinical burden of keratoconus in terms of transplantation
      demand.
discussions:
- discussion_id: gap_kc_systemic_associations
  prompt: >-
    Which of the many reported systemic associations of keratoconus are causal,
    which are confounded by shared exposure (above all eye rubbing), and is the
    reported inverse association with diabetes mellitus real?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Chronic Mechanical Eye Rubbing
  - pathophysiology#Loss of Corneal Biomechanical Rigidity
  rationale: >-
    A dedicated review finds the list of reported systemic associations "very
    long", with atopy, Down syndrome and connective tissue disease the most
    frequently cited. These are not mechanistically equivalent: the atopy
    association is plausibly mediated entirely by itch-driven eye rubbing
    (already modelled as an environmental factor and a pathophysiology node),
    the connective-tissue association has direct genetic support in this entry
    (the GWAS implicates COL12A1, COL6A1, COL1A1 and COL5A1, whose pathogenic
    variants cause Ehlers-Danlos and osteogenesis imperfecta subtypes), and the
    Down-syndrome association is quantitatively unresolved (reported
    prevalences 0-71%). Separately, diabetes mellitus is reported as a candidate
    *protective* factor - mechanistically attractive because non-enzymatic
    glycation cross-links stromal collagen, the same chemistry riboflavin/UV-A
    cross-linking supplies therapeutically - but it is not established. These
    pairs are candidates for structured kb/comorbidities/ entries once the
    direction and confounding structure are settled; they are deliberately not
    asserted as comorbidity entries here.
  proposed_experiments:
  - experiment_id: exp_kc_atopy_rubbing_mediation
    name: Mediation analysis of the atopy association
    description: >
      Cohort or Mendelian-randomisation analysis testing whether the
      atopy-keratoconus association survives adjustment for objectively
      quantified eye-rubbing exposure.
    decision_criterion: >
      Attenuation of the atopy effect to the null after adjustment for rubbing
      would establish rubbing as the mediator and argue against curating atopy
      as an independent comorbidity.
  - experiment_id: exp_kc_diabetes_protective_mr
    name: Mendelian randomisation of the diabetes inverse association
    description: >
      Mendelian randomisation using type 2 diabetes and glycaemic-trait
      instruments against keratoconus liability, to distinguish a genuine
      protective effect of glycation cross-linking from detection bias in
      diabetic eye-care cohorts.
    decision_criterion: >
      A significant protective MR estimate consistent in direction with the
      glycation-cross-linking mechanism would support curating an inverse
      comorbidity; a null estimate would attribute the observation to
      surveillance bias.
  evidence:
  - reference: PMID:37374145
    reference_title: "Systemic Associations with Keratoconus."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We found that atopy, Down syndrome, and various connective tissue
      diseases were the most frequently cited associations in our broad
      literature search.
    explanation: >-
      Identifies the three most frequently cited systemic associations, which
      are the subject of this gap.
  - reference: PMID:37374145
    reference_title: "Systemic Associations with Keratoconus."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Additionally, Diabetes Mellitus has been increasingly studied as a
      possible protective factor against keratoconus.
    explanation: >-
      States the candidate inverse association while marking it as under study
      rather than established; typed PARTIAL for that reason.
  - reference: PMID:37374145
    reference_title: "Systemic Associations with Keratoconus."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      However, the mechanisms underlying the development of keratoconus are
      largely unknown.
    explanation: >-
      Confirms that the mechanistic basis of these associations remains open,
      justifying KNOWLEDGE_GAP rather than curated comorbidity entries.
  - reference: PMID:33649486
    reference_title: "A multi-ethnic genome-wide association study implicates collagen matrix integrity and cell differentiation pathways in keratoconus."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      COL6A1, COL1A1, and COL5A1 have been described in individuals with
      different subtypes of the connective tissue
    explanation: >-
      Supplies the shared-collagen-gene rationale that distinguishes the
      connective-tissue association from the rubbing-confounded ones.
- discussion_id: gap_kc_primary_pathomechanism
  prompt: >-
    What is the primary pathomechanism of keratoconus - is the matrix
    degradation that thins the stroma driven principally by the polygenic
    collagen/cell-differentiation susceptibility, by rubbing-induced mechanical
    and inflammatory injury, or by an obligate interaction of the two?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Polygenic Corneal Matrix Susceptibility
  - pathophysiology#Corneal Stromal Extracellular Matrix Degradation
  rationale: >-
    Two authoritative sources published seven years apart both state plainly
    that the underlying mechanism is unknown, while independently confirming
    that genetic and environmental contributions both exist. The causal edge
    from susceptibility to matrix degradation is therefore modelled as
    INDIRECT_UNKNOWN_INTERMEDIATES. Resolving the relative weight of the two
    arms determines whether rubbing-cessation counselling is disease-modifying
    or merely adjunctive, and whether genetic risk stratification could target
    early cross-linking.
  proposed_experiments:
  - experiment_id: exp_kc_rubbing_prs_interaction
    name: Gene-environment interaction cohort
    description: >
      Prospective cohort with objective (not self-reported) eye-rubbing
      quantification, stratified by polygenic risk score, testing for
      gene-environment interaction on topographic progression.
    decision_criterion: >
      A significant interaction term between rubbing exposure and polygenic risk
      score on progression rate would support an obligate two-hit model over
      either arm acting alone.
  - experiment_id: exp_kc_tear_proteome_biomechanics_timecourse
    name: Tear proteome versus biomechanics time course
    description: >
      Paired tear-proteome and corneal-biomechanics time series in incident
      cases, to establish whether protease and cytokine elevation precedes or
      follows measurable biomechanical loss.
    decision_criterion: >
      Mediator elevation preceding biomechanical change would place the
      inflammatory node upstream as a driver rather than a consequence.
  evidence:
  - reference: PMID:24357835
    reference_title: "The pathogenesis of keratoconus."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The cause and underlying pathological mechanism are unknown, but both
      environmental and genetic factors are thought to contribute to the
      development of the disease.
    explanation: >-
      States the knowledge gap explicitly while affirming dual genetic and
      environmental contribution.
  - reference: PMID:33649486
    reference_title: "A multi-ethnic genome-wide association study implicates collagen matrix integrity and cell differentiation pathways in keratoconus."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Keratoconus is characterised by reduced rigidity of the cornea with
      distortion and focal thinning that causes blurred vision, however, the
      pathogenetic mechanisms are unknown.
    explanation: >-
      The largest genetic study of the disease still describes the pathogenetic
      mechanisms as unknown.
- discussion_id: controversy_kc_inflammatory_status
  prompt: >-
    Should keratoconus continue to be classified as a "non-inflammatory" corneal
    ectasia, given consistently elevated tear IL-6, TNF-alpha, and MMP-9?
  kind: CONTROVERSY
  status: OPEN
  attaches_to:
  - pathophysiology#Ocular Surface Inflammatory Mediator Release
  rationale: >-
    The canonical 1998 definition calls keratoconus a "bilateral noninflammatory
    corneal ectasia", and that wording persists in textbooks and in the MONDO
    synonym "noninflammatory corneal thining". Biochemical evidence accumulated
    since then documents a reproducible cytokine and matrix-metalloproteinase
    signature in the tear film, and a 2022 review states the condition has more
    recently been associated with ocular inflammation. The disagreement is
    substantive rather than semantic: if a low-grade inflammatory arm is causal
    rather than epiphenomenal, anti-inflammatory or anti-protease therapy
    becomes a rational adjunct to cross-linking, and this entry's
    inflammatory-mediator node would move from modulator to driver.
  evidence:
  - reference: PMID:9493273
    reference_title: "Keratoconus."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Keratoconus is a bilateral noninflammatory corneal ectasia with an
      incidence of approximately 1 per 2,000 in the general population.
    explanation: States the classical non-inflammatory definition.
  - reference: PMID:25931166
    reference_title: "Keratoconus: an inflammatory disorder?"
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Recent studies have shown a significant role of proteolytic enzymes,
      cytokines, and free radicals; therefore, although keratoconus does not
      meet all the classic criteria for an inflammatory disease, the lack of
      inflammation has been questioned.
    explanation: >-
      Directly challenges the non-inflammatory classification on biochemical
      grounds.
  - reference: PMID:34991971
    reference_title: "Keratoconus: An updated review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Traditionally, the condition has been described as a noninflammatory
      disease; however, more recently it has been associated with ocular
      inflammation.
    explanation: >-
      A contemporary review confirms the classification is actively contested.
  - reference: PMID:38830186
    reference_title: "The Pathophysiology of Keratoconus."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Immunologic changes have also been identified in keratoconus, challenging
      the traditional view of the condition as noninflammatory.
    explanation: >-
      A 2025 pathophysiology review states the challenge to the noninflammatory
      classification in terms, independently of the 2015 and 2022 sources above.
  - reference: PMID:38830186
    reference_title: "The Pathophysiology of Keratoconus."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Elevated levels of proinflammatory cytokines like IL-1b, IL-6, IL-17, and
      TNF-α have been observed, along with increased apoptosis of keratocytes.
    explanation: >-
      Supplies the specific cytokine profile (extending the tear-film
      IL-6/TNF-alpha signature with IL-1b and IL-17) on which the challenge
      rests.
- discussion_id: openq_kc_molecular_disease_modifying_therapy
  prompt: >-
    Can a molecular (non-photochemical) disease-modifying therapy for
    keratoconus be developed that restores stromal matrix integrity rather than
    stiffening the residual stroma, and what target should it engage?
  kind: OPEN_QUESTION
  status: OPEN
  attaches_to:
  - pathophysiology#Corneal Stromal Extracellular Matrix Degradation
  - pathophysiology#Loss of Corneal Biomechanical Rigidity
  rationale: >-
    Every established treatment is either photochemical stiffening (CXL),
    optical compensation (lenses), or tissue replacement (keratoplasty); none
    reverses the underlying matrix loss. Non-light-based chemical cross-linkers
    are under investigation as alternatives, which keeps the therapeutic
    strategy anchored to stiffening rather than matrix restoration. Regenerative
    approaches - notably limbal or mesenchymal stem-cell exosome cargo aimed at
    ECM restoration - have been proposed but rest so far on preprint-stage
    bioinformatic prioritisation rather than peer-reviewed experimental or
    clinical evidence, so no candidate cargo is asserted in this entry.
  proposed_experiments:
  - experiment_id: exp_kc_exosome_cargo_validation
    name: Peer-reviewed validation of prioritised exosome cargo
    description: >
      Experimental validation, in keratoconus corneal tissue and in a model of
      stromal thinning, of extracellular-vesicle cargo nominated by
      computational prioritisation from keratoconus transcriptomes.
    decision_criterion: >
      Restoration of stromal extracellular-matrix composition and thickness by a
      defined cargo would establish a matrix-restorative target.
  - experiment_id: exp_kc_restorative_vs_cxl
    name: Matrix-restorative candidate versus standard cross-linking
    description: >
      Head-to-head comparison of a matrix-restorative candidate against standard
      epithelium-off cross-linking on corneal biomechanics and topographic
      progression.
    decision_criterion: >
      Non-inferior progression control with superior recovery of corneal
      thickness would favour a restorative over a stiffening strategy.
  evidence:
  - reference: PMID:42430076
    reference_title: "The Science and Clinical Evolution of Corneal Cross-Linking: Mechanism of Action, Ultra-Structural Changes, Clinical Indications, and Emerging Treatment Strategies."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      In addition, novel chemical cross-linkers are being investigated as
      non-light-based alternatives for corneal stabilization.
    explanation: >-
      Confirms that the emerging therapeutic pipeline remains oriented towards
      stabilisation rather than restoration, framing the open question.
datasets: []

📚

References & Deep Research

References

11

PMID:34991971

Keratoconus: An updated review.

No top-level findings curated for this source.

PMID:24357835

The pathogenesis of keratoconus.

No top-level findings curated for this source.

PMID:33649486

A multi-ethnic genome-wide association study implicates collagen matrix integrity and cell differentiation pathways in keratoconus.

No top-level findings curated for this source.

PMID:42228627

Global Consensus on Keratoconus and Ectatic Diseases-Edition 2.

No top-level findings curated for this source.

PMID:25738235

Global consensus on keratoconus and ectatic diseases.

No top-level findings curated for this source.

PMID:37374145

Systemic Associations with Keratoconus.

No top-level findings curated for this source.

PMID:9493273

Keratoconus.

No top-level findings curated for this source.

PMID:38830186

The Pathophysiology of Keratoconus.

No top-level findings curated for this source.

PMID:39448666

Keratoconus.

No top-level findings curated for this source.

PMID:39671084

Definition of Progressive Keratoconus: A Systematic Review.

No top-level findings curated for this source.

PMID:39535071

Developing and validating a comprehensive polygenic risk score to enhance keratoconus risk prediction.

No top-level findings curated for this source.

Deep Research

1

Keratoconus — Claude Code literature sweep ▸

Keratoconus — Claude Code literature sweep

Disease: Keratoconus (MONDO:0015486, HP:0000563) KB entry: kb/disorders/Keratoconus.yaml Provider: Claude Code literature sweep (PubMed E-utilities, esearch + esummary) Run date: 2026-07-31 Context: PR #7128, review item 🟡 #3 ("no deep-research artifact for a new entry")

Method

No third-party deep-research provider (Falcon / Asta / OpenScientist / Perplexity) was available in this runner, so this is a Claude Code literature sweep rather than a DR provider report. Ten independent PubMed queries were issued, one per coverage axis, each retrieving the top 6 relevance-ranked hits. This is a multi-modal sweep — each axis is blind to what the others surface, which is what makes it a coverage audit rather than a single-query snapshot.

Because the axes were chosen to probe the specific coverage gaps the PR review named (phenotypes, histopathology, comorbidities, clinical trials, genetics depth), a "nothing new" result on an axis is itself a finding.

Provenance discipline. Every PMID below came back from a live PubMed query — none was recalled from model memory. Every PMID that was mined into the KB entry was first cached with just fetch-reference, and every snippet was verified as an exact whitespace-normalized substring of that cache before commit. Titles for PMIDs that were surfaced but not mined are reproduced from the esummary payload and have not been independently re-verified — treat them as leads, per the CLAUDE.md DR guidance.

Queries

Axis	PubMed query
biomechanics	`keratoconus AND corneal biomechanics AND (review[pt])`
tear proteomics / inflammation	`keratoconus AND (tear OR proteomic) AND (cytokine OR MMP OR inflammation)`
atopy / eye rubbing	`keratoconus AND (eye rubbing OR atopy OR allergic conjunctivitis)`
comorbidity	`keratoconus AND (comorbidity OR association) AND (sleep apnea OR Down syndrome OR connective tissue)`
hydrops management	`acute corneal hydrops keratoconus management`
keratoplasty outcomes	`keratoconus AND (keratoplasty OR DALK OR penetrating) AND outcomes`
cross-linking evidence	`corneal collagen crosslinking keratoconus AND (randomized OR meta-analysis)`
progression definition	`keratoconus progression definition criteria`
pediatric	`pediatric keratoconus progression`
genetics	`keratoconus genetics AND (GWAS OR polygenic risk score)`

Findings acted on in this PR

Four sweep hits were material enough to mine into the entry. All four were cached with just fetch-reference and their snippets verified.

1. `PMID:42228627` — Global Consensus on Keratoconus and Ectatic Diseases, Edition 2 (Cornea, 2026)

The most consequential finding of the sweep. The entry cited the 2015 first edition (PMID:25738235). Edition 2 was published 2026-07 and supersedes it: 128 ophthalmologists from 6 continents and 12 international societies, 4 Delphi rounds, covering definition, diagnosis, staging, and progression criteria. Curating a brand-new entry against a superseded consensus would have been a real defect.

→ Mined into diagnosis as the current framework, with the 2015 edition retained (not replaced) because it is the consensus underlying most of the intervening literature this entry cites.

2. `PMID:37374145` — Systemic Associations with Keratoconus (Life, 2023)

Directly addresses the review's comorbidities gap. Names atopy, Down syndrome and connective tissue disease as the most frequently cited associations, and reports diabetes mellitus as a candidate protective factor.

→ Mined as a KNOWLEDGE_GAP discussion (gap_kc_systemic_associations) rather than as comorbidity assertions. Reasoning: the three "positive" associations are not mechanistically equivalent — the atopy association is plausibly mediated entirely by itch-driven eye rubbing (already modelled as both an environmental factor and a pathophysiology node), so asserting it as an independent comorbidity would double-count a single causal pathway. The review itself states the mechanisms "are largely unknown". The gap carries two proposed experiments (rubbing-adjusted mediation analysis; MR for the diabetes inverse association) that would resolve which pairs deserve kb/comorbidities/ entries.

3. `PMID:33649486` full text (already cached) — per-gene GWAS mining

Not a new PMID, but the sweep's genetics axis prompted a re-read of the cached full text (not just the abstract) of the multi-ethnic GWAS. Review item 🟡 #4 was correct that this source was under-mined: it supports named per-gene records with quotable association statistics.

→ Added COL12A1 (strongest coding signal: rs35523808 p.Glu2160Val, and collagen XII localises to Bowman's layer — connecting the locus directly to the "Anterior Limiting Membrane Rupture" node), FNDC3B, ZNF469, ALDH3A1, ITGA2; and added genuine association evidence (Table 1 rows) to the pre-existing COL5A1 and LOX records.

The LOX/VSX1 typing inconsistency the review flagged is resolved by this: LOX now rests on a genome-wide significant association (rs840464) plus an eQTL effect on its own transcription, whereas VSX1 still rests only on the shared "analysed markers" sentence — so SUSCEPTIBILITY vs DISPUTED no longer rest on the same evidence.

4. `HP:6001232` Corneal iron line / `HP:0012040` Corneal stromal edema

Not literature, but found while closing the phenotype gap: HPO does have a term for the Fleischer ring (HP:6001232, whose own definition names keratoconus as a typical setting) and for the stromal oedema of acute hydrops (HP:0012040). Both verified present in the local sqlite:obo:hp adapter.

→ Both added as phenotypes; a histopathology section was added for stromal thinning, Bowman's-layer breaks and epithelial basement-membrane iron deposition (all unbound — NCIT has no corneal morphologic finding terms for these).

Findings NOT acted on, and why

Recording these explicitly so the next curator does not re-run the same searches.

Lead	Axis	Why deferred
~~`PMID:39448666` Keratoconus (Nat Rev Dis Primers, 2024)~~	atopy/rubbing	Now mined (round 3) — supplied the UV-light-exposure and contact-lens-wear `environmental:` records.
~~`PMID:38830186` The Pathophysiology of Keratoconus (Cornea, 2025)~~	biomechanics	Now mined (round 3) — supplied two new pathophysiology nodes (`Corneal Oxidative Stress`, `Keratocyte Apoptosis`), a biomechanical-primacy evidence item, and two REFUTE items strengthening the inflammatory-status controversy.
~~`PMID:39535071` polygenic risk score (Hum Mol Genet, 2025)~~	genetics	Now mined (round 3) — added as two evidence items on the `Polygenic susceptibility architecture` genetic record. The cohort ambiguity flagged here was handled by quoting the biobank by name in each snippet (EstBB OR 2.28; UKB AUC 0.84→0.88) rather than stating a bare AUC.
~~`PMID:39671084` Definition of Progressive Keratoconus: systematic review (Cornea, 2025)~~	progression	Now mined (round 3) — supplied a "Documented progression (the cross-linking indication)" `progression:` record; typed the lack-of-unified-criteria conclusion PARTIAL, and cross-referenced the Edition 2 consensus in the diagnosis section rather than presenting it as superseded.
`PMID:39681212` Corneal cross-linking (Prog Retin Eye Res, 2025); `PMID:37938377` epi-on vs epi-off meta-analysis; `PMID:36094374` oxygen in CXL	CXL evidence	The entry's CXL treatment is already evidenced. These would deepen protocol-level detail, which is below the abstraction level this KB curates.
`PMID:39943883` PK vs DALK meta-analysis (27,018 eyes); `PMID:27802912`	keratoplasty	Would support a surgical-outcomes elaboration of the existing keratoplasty treatment. Not a mechanism claim.
`PMID:38317314` Management of acute corneal hydrops (2024)	hydrops	Management-level; the hydrops mechanism is already curated from `PMID:24491416` and was split into two atomic nodes in this PR.
`PMID:37227479` Ocular manifestations of OSA meta-analysis	comorbidity	A genuine candidate comorbidity (OSA-keratoconus) not covered by `PMID:37374145`. Left as a lead; it belongs in the systemic-associations gap discussion's scope.
`PMID:33463562`, `PMID:39396644`, `PMID:36973341` pediatric keratoconus	pediatric	Pediatric-onset keratoconus progresses faster and is a distinct management context. Not curated — the entry does not currently model onset-stratified subtypes, and adding one is a scoping decision beyond this review round.
Clinical trials (`clinical_trials` section)	—	Deliberately not added. The review suggested an NCT record for the US multicentre CXL trial (`PMID:28495149`). ClinicalTrials.gov queries returned several plausible CXL trials, but none could be confirmed as that trial (the closest enrollment/design match, `NCT00567671`, is an Emory single-site study — not the multicentre trial). Guessing an NCT here would be exactly the misattribution failure the repository's evidence SOP exists to prevent. Left uncurated pending a verifiable registry link.

Coverage assessment after this round

Section	Before	After
`phenotypes`	4	6
`histopathology`	absent	3 findings
`genetic`	5 records, 1 real source	10 records, GWAS-anchored
`diagnosis`	1	2 (current consensus)
`discussions`	2	3
`comorbidities` (separate files)	absent	still absent — deliberately, see above
`clinical_trials`	absent	still absent — deliberately, see above

Round 3 — mining pass over cached-but-unconsumed references

Prompted by the second PR review, which flagged that four references shipped in references_cache/ in this PR were consumed by zero evidence items. All four are now mined; no new literature search was run and no new cache files were fetched.

Section	After round 2	After round 3
`pathophysiology`	12 nodes	14 nodes (`Corneal Oxidative Stress`, `Keratocyte Apoptosis`)
`environmental`	2	4 (UV exposure, contact lens wear)
`progression`	1 record	2 records (progression definition / CXL indication)
`genetic` evidence on the polygenic record	1 item	3 items (PRS validation in two biobanks)
verified snippets	73/73	85/85
cached-but-unconsumed references	4	0

Both new pathophysiology nodes carry a notes: stating which upstream edge was deliberately not asserted and why — the source reports oxidative stress and keratocyte apoptosis without establishing what drives either, and "along with" is co-observation, not causation. The Anterior Limiting Membrane Rupture → Loss of Corneal Biomechanical Rigidity edge was also recalibrated from DIRECT to INDIRECT_UNKNOWN_INTERMEDIATES (review suggestion 2): the snippets establish the lesion histopathologically, not its biomechanical consequence, and Bowman's layer is ablated wholesale in PRK without inducing ectasia.

Open follow-ups worth issues

keratoconus_corneal_ectasia mechanism module. Keratoconus carries both an HP and a MONDO id and is used as a phenotype by at least five other entries (Ehlers-Danlos_Syndrome, Arterial_Tortuosity_Syndrome, Spondylodysplastic_Ehlers-Danlos_Syndrome, CRB1_Retinal_Dystrophies, GUCY2D-Related_Retinopathy). That is the "disease-like phenotype" pattern that glaucoma, cataract and osteoporosis each model as a disorder entry plus a kb/modules/ module. Raised by the PR reviewer (suggestion 13) and endorsed here.
MAXO NTR for corneal collagen cross-linking. Neither MAXO nor NCIT codes CXL; the entry uses NCIT:C15301 Phototherapy + CHEBI:17015 riboflavin as an interim composition.
OSA-keratoconus (PMID:37227479) as a candidate comorbidity pair.

Keratoconus

Ask OpenScientist

OpenScientist Report

Inheritance

Discussions and Knowledge Gaps

Pathophysiology

Histopathology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Environmental Factors

Diagnosis

Progression

Prevalence

Source YAML

References & Deep Research

References

Deep Research

Keratoconus — Claude Code literature sweep

Method

Queries

Findings acted on in this PR

1. `PMID:42228627` — Global Consensus on Keratoconus and Ectatic Diseases, Edition 2 (Cornea, 2026)

2. `PMID:37374145` — Systemic Associations with Keratoconus (Life, 2023)

3. `PMID:33649486` full text (already cached) — per-gene GWAS mining

4. `HP:6001232` Corneal iron line / `HP:0012040` Corneal stromal edema

Findings NOT acted on, and why

Coverage assessment after this round

Round 3 — mining pass over cached-but-unconsumed references

Open follow-ups worth issues

Ask OpenScientist

OpenScientist Report

Inheritance

Discussions and Knowledge Gaps

Pathophysiology

Histopathology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Environmental Factors

Diagnosis

Progression

Prevalence

Source YAML

References & Deep Research

References

Deep Research

Keratoconus — Claude Code literature sweep

Method

Queries

Findings acted on in this PR

1. PMID:42228627 — Global Consensus on Keratoconus and Ectatic Diseases, Edition 2 (Cornea, 2026)

2. PMID:37374145 — Systemic Associations with Keratoconus (Life, 2023)

3. PMID:33649486 full text (already cached) — per-gene GWAS mining

4. HP:6001232 Corneal iron line / HP:0012040 Corneal stromal edema

Findings NOT acted on, and why

Coverage assessment after this round

Round 3 — mining pass over cached-but-unconsumed references

Open follow-ups worth issues

1. `PMID:42228627` — Global Consensus on Keratoconus and Ectatic Diseases, Edition 2 (Cornea, 2026)

2. `PMID:37374145` — Systemic Associations with Keratoconus (Life, 2023)

3. `PMID:33649486` full text (already cached) — per-gene GWAS mining

4. `HP:6001232` Corneal iron line / `HP:0012040` Corneal stromal edema