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  • 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 vesicle 2. 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 Keratitis Cataracts 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

    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

  • 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’ Anomaly Kerato-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