developmental abnormalities of the anterior segment · mammalian eye development optic vesicle...
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Developmental
Abnormalities
of the Anterior
Segment
Nikos Kozeis MD, MSc, PhD, PostDoc, FICO, FEBO, MRCOphth
‘’Ophthalmica’’ Eye Institute
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Anterior Segment Developmental Anomalies
• Development
• Genetics
1. Aniridia + associated syndromes
2. Posterior Embryotoxon
3. Rieger’s Anomaly +Axenfeld-Rieger syndrome
4. Peters Anomaly
5. Peters Plus syndrome
6. (Sclerocornea)
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Mammalian eye development
optic vesicle
Surface
ectoderm
lens
placode
Neural
ectoderm
Optic cup
Precursor of
pigmented
retina
lens
pit
Days post
coitum neural retina
Cornea
lens vesicle
primary fibre
cells
optic stalk
lens
epithelium lens
fibres
vitreous
body
Cvekl &
Piatigorsky, 1996
brain
Future
Optic nerve
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Gould DB et. al. Anterior segment development relevant to glaucoma Int. J. Dev. Biol. 2004;48:1-13
Optic vesicle2. Neurectoderm
3. Periocular mesenchyme
= neural crest + paraxial
mesoderm-derived cells
1.Surface ectoderm
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Gould DB et. al. Anterior segment development relevant to glaucoma
Int. J. Dev. Biol. 2004;48:1-13
Optic
vesicle 1. Surface ectoderm
- Lens
- Conjunctival & corneal epithelium
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2. Neurectoderm
– Neural retina + RPE
– Posterior iris & ciliary body epithelium
– Non-pigmented ciliary epithelium
– Zonules
Optic
vesicle
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3. Periocular mesenchyme
•Neural crest
– corneal stroma, keratocytes + endothelium
– most of sclera
– anterior iris stroma
– ciliary muscle & stroma
– Uveal Melanocytes
– Chamber angle & Schlemm’s
•Paraxial mesoderm
– Temporal Sclera
– Endothelium of BVs
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Human
gene
Type + site of
action
Locus Disease
PAX6 Tr Panoc 11p13 Aniridia, ASDA, P,C, ONH, Foveal hypoplasia,
keratitis, G. ICA
PITX2 Tr NC 4q25 ASDA, G. A-RS. interacts with TGFβ. ICA.
FOXC1
Forkhead
Tr NC 6p25 ASDA, G, A-RS, ICA.
PITX3 Tr 10q25 ASDA, C
MAF Tr L 16q23 ASDA, C
FOXE3 Tr L 1p23 Lens-cornea separation failure. PAX6 interaction
CYP1B1 Enz 2p22 G. Posterior ulcer of Von Hippel. ICA
LMX1B Tr NC 9q34 Nail-patella syndrome. G
EYA1 Tr ?NC 8q13 G, microphthalmos. interacts with PAX6
G=glaucoma, ASDA=Ant Sec Dev Anom P=Peters’, C=cataract, ONH=ON Hypoplasia
A-RS=Ax-Reig synd, ICA= Irido-corneal adhesion(+other genes!), Panoc= panocular.
NC=Neur crest, L=Lens
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Posterior Embyrotoxon
Posterior Ulcer of Von Hippel
Irido-corneal adhesions
Corneal
Opacity
Central
Peripheral
Iris Hypoplasia
Cataract“Primary”
Glaucoma
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What are the classic phenotypes of anterior
segment dysgenesis?
Prominent
Schwalbes
ring
Iris strands
attached to
Schwalbes
ring
Hypoplasia
iris stroma
Posterior
corneal
defect and
leukoma
Iris
adhesions
to leukoma
+/-
cataracts
1. Lens
apposition to
leukoma or ant
polar cataract .
2. corneal
degeneration
Posterior
Embyrotoxon+
Axenfeld’s
Anomaly+ +
Riegers Anomaly + + +
Peters Anomaly + + +
Sclerocornea ? ? ? ?
Aniridia + +
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What is the genotype – phenotype
correlation?
• PITX2 Rieger syndrome
Iris hypoplasia
Iridogoniodysgenesis
• FKHL7 Rieger anomaly Axenfeld anomaly
Iris hypoplasia Posterior embryotoxon
Primary congenital glaucoma
Peters’ anomaly
• PAX6 Aniridia Peters’ anomaly KeratitisCataracts Foveal hypoplasia
Congenital nystagmus Ectopia pupillae
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ASDA
Sclero-
cornea
Congenital
Hereditary
Endothelial
Dystrophy
Peters’
anomaly
Axenfeld-
Rieger
Anomaly
Primary
Congenital
Glaucoma
Irido-
gonio-
dysgenesis
Megalo-
cornea
Aniridia
Unclassified
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Aniridia
Heterozygous loss-of-function
mutations of PAX6
1:70,000
AD
AR with syndromes
Sporadic
11p13 deletion
Partial or complete
Lim et.al. Curr Opin
Ophthalmol.
2017;28(5):436-47
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Macular
hypoplasia
Optic Disc
hypoplasia /
dysplasia
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Birth
3 years +/- 20
operations
Glaucoma
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Aniridia-Associated Keratopathy 25%Eslani M et.al. IOVS. 2017;58(12):5507-5517
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Normal Vascular
limbus
Avascular
cornea
sFLT
staining
Vascular
cornea
Aniridia
sFLT
staining
sFLT is first six domains of VEGF receptor 1
sFLT sequesters VEGF and angiogenesis
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Congenital Central Corneal Opacities 13% Lee2017 http://dx.doi.org/10.1016/j.ajo.2017.10.017
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Lee2017 http://dx.doi.org/10.1016/j.ajo.2017.10.017
Subluxation
of the lens
Axial congenital
Cataract 13%
Progressive
Cortical
Cataract <80%
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Surgery in Aniridia
• Glaucoma
– Goniotomy
– ‘Enhanced’ Filtration Sx
– Tubes
• Cataract
– Pre-op assessment VA
– IOLs
• Corneal opacity
Tsai JS et. al. ..progressive anterior fibrosis.. Am J Ophthalmol. 2005;140:1075-9
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Aniridia Syndromes
• WAGR
Wilms tumours, Aniridia, G-U anomalies, MRetardation
• Gillespie’s
Aniridia, MR, cerebellar ataxia.
2 PAX 6 cases. Others ITPR1 mutations
• Aniridia, absent patellae
• Aniridia, anophthalmos, microcephaly
• 13 others
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Always in aniridia check for …
Glaucoma, cataract, corneal problems
Renal cancer: Wilms tumour mostly sporadic cases
3/12 to 5 yrs, 6/12 to 10, annually to 16
• Abdominal Renal Palpation
• Renal U/S
• Blood in urine
FISH/other cytogenetics & Mutation Analysis
Refraction !!! Low Vision assessment !!!
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• Isolated
– 6.8 % of 723 OPD attenders had
PE
– Glaucoma
• Alagille’s syndrome
Posterior Embryotoxon
Prominent Schwalbe’s ring
Rennie CA et. al.
Eye 2005;19:396-397
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Facial Dysmorphism
Intrahepatic cholestasis
Pulmonary stenosis
Dev. Delay, Renal abnormalities
90% have Optic Disc Drusen
90% have Post. Embryotoxon
?% RPE disturbance
Good Visual Prognosis
Alagille’s Syndrome
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Axenfeld’s Anomaly
Posterior embryotoxon + iris bridges
• Glaucoma in 50%
• Some AD pedigrees
• Occasional systemic
abnormalities
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Rieger’s Anomaly
•Very variable phenotype
•Corneal opacities and
cataract
Iris Hypoplasia
Featureless iris
Corectopia
Pseudo-polycoria
Ectropion Uveae
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Axenfeld-Rieger Anomaly
• AD
• Glaucoma in 60%
• Myopia and retinal
detachment
• Corneal opacities and
cataract
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Maxillary hypoplasia
Hernias
Hypospadias
Pituitary Hypoplasia
Anal Stenosis
PAX6 – 11p13
PITX2 - 4q25
FOXC1- 6p25
RIEG2 - 13q14
Axenfeld - Rieger Syndrome
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Dental anomalies
Microdontia
Decreased number
Absent 1st permanent molar
Other absent teeth
1 x Cerebellar Hypoplasia
1 x small Sella
2 x large cisterna
1 x dev delay
Axenfeld-Rieger Syndrome
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GONIOSCOPIC VIEW
Usually bilateral
Central corneal opacities
Lens abnormalities
Iris strands
Others
Peters’ AnomalyKerato-Irido-Lenticular Dysgenesis: KILD
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Lens-cornea Fusion
Gonioscopy of infant with Peters’ anomaly
Iris Strands
Peters’ Anomaly
PAX6, PITX2, CYP1B1
FOXE3: lens separation
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Peters’ Anomaly
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Peters’ Plus
Mutations in B3GALTL
Short stature
Brachymorphic
Cleft lip and palate Round face
Smooth philtrum Micrognathia
Abnormal ears
Developmental delay
AR
Syndromes with
Peters’ anomaly
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Oculo-Auricular
SyndromeNKX5-3 Homeobox Gene
Schorderet DF et. al.2008 (Lausanne)
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• “KILD”
• AR?
• Central and peripheral corneal opacities
Often ‘ringed’, bilateral
?related to Congenital Corneal ‘Perforation’ and Peters’
• Glaucoma frequent
• Systemic abnormalitiesoccasionally
“Sclerocornea”Most are Peters’ variants?
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Corneal Grafting in ASDAs
• Bilateral cases only?
• May clear spontaneously: Give time!
• Pre-op assessment
– U/S, UBM, VEPs, Developmental assessment
• Full parental consent
• Expert team
Michaeli A et. al (Toronto: 78% clarity success for all cases, 50% for sclerocornea
J Ped. Ophthalmol Strabismus. 2005;42:34-44
Small grafts
Young material, oversized donor
Vitreolensectomy often needed
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