Developmental

Abnormalities

of the Anterior

Segment

Nikos Kozeis MD, MSc, PhD, PostDoc, FICO, FEBO, MRCOphth

‘’Ophthalmica’’ Eye Institute

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)

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

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

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

2. Neurectoderm

– Neural retina + RPE

– Posterior iris & ciliary body epithelium

– Non-pigmented ciliary epithelium

– Zonules

Optic

vesicle

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

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

Posterior Embyrotoxon

Posterior Ulcer of Von Hippel

Irido-corneal adhesions

Corneal

Opacity

Central

Peripheral

Iris Hypoplasia

Cataract“Primary”

Glaucoma

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 + +

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

ASDA

Sclero-

cornea

Congenital

Hereditary

Endothelial

Dystrophy

Peters’

anomaly

Axenfeld-

Rieger

Anomaly

Primary

Congenital

Glaucoma

Irido-

gonio-

dysgenesis

Megalo-

cornea

Aniridia

Unclassified

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

Macular

hypoplasia

Optic Disc

hypoplasia /

dysplasia

Birth

3 years +/- 20

operations

Glaucoma

Aniridia-Associated Keratopathy 25%Eslani M et.al. IOVS. 2017;58(12):5507-5517

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

Congenital Central Corneal Opacities 13% Lee2017 http://dx.doi.org/10.1016/j.ajo.2017.10.017

Lee2017 http://dx.doi.org/10.1016/j.ajo.2017.10.017

Subluxation

of the lens

Axial congenital

Cataract 13%

Progressive

Cortical

Cataract <80%

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

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

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 !!!

• 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

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

Axenfeld’s Anomaly

Posterior embryotoxon + iris bridges

• Glaucoma in 50%

• Some AD pedigrees

• Occasional systemic

abnormalities

Rieger’s Anomaly

•Very variable phenotype

•Corneal opacities and

cataract

Iris Hypoplasia

Featureless iris

Corectopia

Pseudo-polycoria

Ectropion Uveae

Axenfeld-Rieger Anomaly

• AD

• Glaucoma in 60%

• Myopia and retinal

detachment

• Corneal opacities and

cataract

Maxillary hypoplasia

Hernias

Hypospadias

Pituitary Hypoplasia

Anal Stenosis

PAX6 – 11p13

PITX2 - 4q25

FOXC1- 6p25

RIEG2 - 13q14

Axenfeld - Rieger Syndrome

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

GONIOSCOPIC VIEW

Usually bilateral

Central corneal opacities

Lens abnormalities

Iris strands

Others

Peters’ AnomalyKerato-Irido-Lenticular Dysgenesis: KILD

Lens-cornea Fusion

Gonioscopy of infant with Peters’ anomaly

Iris Strands

Peters’ Anomaly

PAX6, PITX2, CYP1B1

FOXE3: lens separation

Peters’ Anomaly

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

Oculo-Auricular

SyndromeNKX5-3 Homeobox Gene

Schorderet DF et. al.2008 (Lausanne)

• “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?

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

Thank you for your attention