DEVELOPMENTAL GLAUCOMADr. Nidhi Thaker

• Primary glaucomas with associated abnormalities

• All of the primary glaucomas that have associated ocular abnormalities to be forms of anterior segment dysgenesis.

• Neurocristopathies

• Anterior segment dysgeneses are attributed to defects in neural crest migration or differentiation

1. IRIDODYSGENESISa. Aniridiab

b. Congenital iris ectropion syndrome

c. Iridotrabecular dysgenesis (iris hypoplasia)

2. CORNEODYSGENESIS (IRIDOCORNEODYSGENESIS)

a. Axenfeld-Rieger anomalyb. Peters anomalyd. Sclerocornea

e. Congenital hereditary endothelial dystrophyf. Posterior polymorphous dystrophy

g. Megalocornea

AXENFELD-RIEGER SYNDROME

Axenfeld-Rieger Syndrome• Three Eponyms: (A) Axenfeld Anomaly : Limited to peripheral anterior segment defects

(B) Rieger Anomaly: Peripheral abnormalities with additional changes in the iris

(C) Rieger Syndrome: Ocular anomalies plus systemic developmental defects

1. Partial retention of the primordial endothelium (e) on the iris (i) and anterior chamber angle (aca);

2. Incomplete posterior recession of peripheral uvea from trabecular meshwork (tm);

3. Abnormal differentiation between corneal and chamber angle endothelium with a prominent, anteriorly displaced schwalbe line (SL).

4. Development of tissue strands from retained endothelium crossing the anterior chamber angle

• Anterior Chamber Cleavage Syndrome • Mesodermal Dysgenesis Of The Cornea And

Iris

• Contraction of retained endothelium with iris changes of corectopia (c), ectropion uvea (eu), and iris atrophy (ia), which may continue after birth; a tissue strand (ts) can also be seen.

• Incomplete development of trabecular meshwork and Schlemm canal (SC); continued traction on the iris with possible secondary ischemia leads to hole formation (h).

General Features• Bilateral

• Frequent family history of the disorder, with an autosomal dominant mode of inheritance

• No sex predilection

• Frequent systemic developmental defects

• High incidence of associated glaucoma

• Age :birth to adulthood, with most cases recognized in infancy or childhood

Ocular Features CORNEA• Prominent, anteriorly displaced

schwalbe line. • White line on the posterior

cornea near the limbus. • Incomplete, usually limited to

the temporal quadrant; Sometimes 360 degree ; only gonioscopic finding

• Occasional variation in the overall size (i.e, Megalocornea or, less often, microcornea) or shape of the cornea

• Congenital opacities of the central cornea

• Anterior Chamber Angle• Gonioscopic examination; 1. Prominent schwalbe line2. Iridocorneal adhesions 3. The anterior chamber angle is open and the trabecular

meshwork is visible, but the scleral spur is typically obscured by peripheral iris, which inserts into the posterior portion of the meshwork

• Iris• Mild stromal thinning to

marked atrophy with hole formation,

• Corectopia• Ectropion uveae.• When corectopia is present,

the pupil is usually displaced toward a prominent peripheral tissue strand the atrophy and hole formation typically occur in the quadrant away from the direction of the corectopia.

Other ocular abnormalities• Strabismus• Limbal dermoids• Corneal pannus• Cataracts• Congenital ectropion uveae• Congenital pupillary-iris-lens membrane• Peripheral spokelike transillumination defects of the iris• Retinal detachment• Macular degeneration• Chorioretinal colobomas• Choroidal hypoplasia• Hypoplasia of the optic nerve heads

• Glaucoma• More than one half of the patients with the

axenfeld-rieger syndrome develop glaucoma. • Childhood or young adulthood. • The high insertion of peripheral iris into the

trabecular meshwork, appears to be more pronounced in those eyes with glaucoma

• The proposed mechanism of glaucoma in these cases relates to abnormalities of the trabecular meshwork and schlemm canal

Systemic Features• Dental anomalies:Microdontia HypodentiaOligodontia

Facial anomalies :A receding upper lip and prominent lower lipHypertelorismMaxillary hypoplasia with flattening of the midface TelecanthusA broad flat noseMicrognathia mandibular prognathism

• primary empty sella syndrome

• Congenital parasellar arachnoid cyst

• Growth hormone deficiency

• Others:o Redundant periumbilical

skin o Hypospadiaso Oculocutaneous albinismo Heart defectso Middle-ear deafnesso Mental deficiency

Genetic Linkage• Chromosomes :4q25, 6p25, and 13q14.

• Type 1 :Pitx2 on 4q25• Type 2: RIEG2 on 13q14 • Type 3: FOXC1 on 6p25

Differential Diagnosis1. Iridocorneal Endothelial (ICE) Syndrom*2. Posterior Polymorphous Corneal Dystrophy3. Peters anomaly4. Aniridia5. Oculodentodigital Dysplasia6. Ectopia Lentis et Pupillae7. Congenital Microcoria and Myopia

Peters Anomaly• Defect in the neural crest cell migration in the 6 – 8th

wk of fetal development• Present at birth • Usually bilateral• Most cases are sporadic/autosomal recessive/

autosomal dominant transmission • Defects of the ear and auditory system, orofacial

system, heart, genitourinary system, spine, and musculoskeletal system

• Can be caused by mutation in the PAX6, PITX2, CYP1B1, or FOXC1

Clinicopathologic Features• Central corneal

abnormality : hallmark 1. Defect in the descemet

membrane and corneal endothelium with thinning and opacification of the corresponding area of corneal stroma

2. Iris adhesions3. Bowman layer absent

centrally

I. In Peters anomaly not associated with keratolenticular contact or cataract

II. Peters anomaly associated with keratolenticular contact or cataract

III. Peters anomaly associated with Axenfeld-Rieger syndrome

Glaucoma• 50% pts • Infantile glaucoma• Mechanism:o Peripheral anterior synechiae formationo Incomplete development of trabecular

meshwork and schlemm canal

Systemic association• Craniofacial anomalies• CNS anomalies• Fetal alcohol syndrome• Chromosomal abnormaalities• ‘peter plus’ syndrome:o Short-limbed dwarfismo Cleft lip/palateo Learning difficulties

D/Do Other Causes of Central Corneal Opacities in

Infants:• PCG• birth trauma• MPS• congenital hereditary endothelial dystrophy.o Posterior Keratoconuso Congenital Corneal Leukomas and Staphylomas

ANIRIDIA• Aniridia is a bilateral developmental disorder

characterized by the congenital absence of a normal iris.

• Abnormal neuroectodermal development

Classification

AD

2/3rd

No systemic complication

genotype+= phenotype

sporadic

1/3rd

PAX6 MUTATION

WAGAR SYNDROME/Miller synd

AR

1%

Gillespie syndrome

Cerebellar ataxia + MR

Clinicopathologic Features

Iris• Aniridia: variable

severity

• Iris and retinal fluorescein : abnormal iris vascular remodeling that resulted in incomplete iris collarettes and decreased retinal foveal avascular zones

Lids: MGD

Cornea:• Corneal pannus and

opacity begin in the peripheral cornea

• Microcornea , sclerocornea

• Iridocorneal and keratolenticular adhesions

• High CCT • Epibulbar dermoid

Lens• Localized congenital

opacities • progressive • Subluxation

(superior)or congenitally absent, or it may be reabsorbed

Fundus• Foveal Hypoplasia, optic nerve hypoplasia, choroidal

coloboma• Poor visual acuity and nystagmus • Spectral-domain OCT can be used to confirm the presence of

foveal hypoplasia in eyes with aniridia, and this correlates well with visual acuity independent of the iris rim width

Glaucoma• 75% Pts• late childhood and adolescenceMechanism: synechial angle closure

secondary to the pulling of the rudimentary iris tissue by contraction of pre exsisting fibres

Glaucoma in aniridia usually develops after rudimentary iris stump rotates anteriorly to progressively cover the trabecular meshwork

Other ocular and systemic association• Choroidal colobomas• Persistent pupillary membranes• Sclerocornea• Hallermann-streiff syndrome• Small optic nerve heads• Strabismus• Ptosis• Marfan syndrome with cervical ribs ,dental anomalies, Tracheomalacia and delayed closure of the anterior fontanelle• Retinoblastoma

DEVELOPMENTAL GLAUCOMAS WITH ASSOCIATED SYSTEMIC ANOMALIES

Sturge-Weber syndromeNeurofibromatosisMarfan SyndromeWeill-Marchesani syndrome

STURGE WEBER SYNDROME

• Ancephalotrigeminal angiomatosis• Unilateral• Ipsilateral cavernous hemangioma/ facial cutaneous

hemangioma/ leptomeningeal angioma• 30- 70%- Glaucoma• Elevated episcleral venous presssure• CNS symptoms

NEUROFIBROMATOSIS• Most common phakomatosisI. NF 1- von Recklinghausen or peripheral NF– Most common– 1: 3000- 5000– AD, ch 17• Ectropion uvea• Lisch nodules• Optic nerve glioma• Eyelid neurofibroma• Café au lait• Axillary/inguinal freckling• Cutaneous neurofibromas

II. NF2• Central NF• Chromosome 22• Posterior subcapsular cataract in adolescence• Not associated with glaucoma• Bilateral acoustic neuroma• Meningioma, schwannoma, ependymoma

OTHER SYNDROMES WITH ASSOCIATED GLAUCOMA

Chromosomal Anomalies• Trisomy 21• Trisomy 13• Trisomy 18• Turner Syndrome

Trisomy 21: Down Syndrome

• Mental retardation and atypical facies.

• Ocular findings :epicanthus, blepharitis, nystagmus, strabismus, light-colored and spotted irides, keratoconus, cataracts, and congenital glaucoma in infancy, with the typical findings of PCG

Trisomy 13-15: Trisomy D Syndrome• Mental retardation, deafness, heart disease, and

motor seizures• Ocular findings: microphthalmia, coloboma with

cartilage, congenital cataracts, retinal dysplasia, persistent fetal vasculature, and dysembryogenesis of the anterior chamber angle Glaucoma

Trisomy 18: Edwards Syndrome• Anterior position of the iris obstructing the

anterior chamber angle

XO: Turner Syndrome• short stature,• postadolescent females with sexual

infantilism and multiple systemic anomalies.• Ocular findings: ptosis, epicanthus, cataract, strabismus, blue sclera, corneal nebulae, and color blindness Developmental glaucoma is rarely associated

GLAUCOMA ASSOCIATED WITH SYSTEMIC CONGENITAL DISORDERS

Lowe (Oculocerebrorenal) syndrome Stickler Syndrome Zellweger syndrome Hallermann-Streiff syndrome Rubinstein-Taybi (broad thumb) syndrome Oculodentodigital dysplasia Cockayne syndrome Fetal alcohol syndrome

Cystinosis• Autosomal recessive metabolic disorder• Characterized by widespread accumulation of

cystine crystals in ocular and nonocular tissues• Mutation in the gene encoding cystinosin

(CTNS: 17p13)• Pupillary block glaucoma caused by the

cystine accumulation in the iris stroma

Hepatocerebrorenal Syndrome: Zellweger Syndrome

Multisystem congenital disorder characterized by • central nervous system abnormalities• Hepatic interstitial fibrosis• Renal cysts Ocular findings :• Nystagmus• Corneal clouding• Cataracts• Retinal vascular and pigmentary abnormalities,• Optic nerve head lesion• Congenital glaucoma :iridocorneal adhesions may be the

mechanism of the glaucoma

Hallermann-streiff syndrome• Micrognathia and dwarfism • Ocular findings:• Cataracts • Microphthalmos. • Glaucoma may also occur because of absorption of lens

material or associated aniridia or after cataract surgery

Kniest dysplasia• Metatropic dwarfism• Autosomal dominant inheritance • Mutations in the COL2A1 gene • Congenital glaucoma

Lowe syndrome• Oculocerebrorenal syndrome• Autosomal recessive/x-linked disorder • Mental retardation, renal rickets, aminoaciduria,

hypotonia, acidemia,irritability. • Cataract• Glaucoma :secondary to removal of concurrent

congenital cataracts. Anterior insertion of the iris, narrowing of the ciliary body band, and decreased visibility of the scleral spur

• Microphthalmia, strabismus, nystagmus, miosis, and iris atrophy.

13-year-old boy with Lowe syndrome and glaucoma controlled with medication use. He has aphakia in both eyes after removal of congenital cataracts, and has small stature, developmental delay, and esotropia.

Mucopolysaccharidoses• The MPS constitute a group of inherited disorders

caused by deficiency of specific lysosomal enzymes needed for the degradation of glycosaminoglycans, or mucopolysaccharides

• The accumulation of partially degraded glycosaminoglycans causes interference with cell, tissue, and organ function.

•Hurler syndrome• autosomal recessive disease with central nervous

system, skeletal, and visceral abnormalities• ocular finding :1. corneal clouding2. Glaucoma has also been reported in Hurler

syndrome and was thought to result from mucopolysaccharide-containing cells in the aqueous outflow system

3. open-angle glaucoma4. IOP returned to normal after bone marrow

transplantation

• Patients with mucopolysaccharidosis type VI, the Maroteaux-Lamy syndrome

• Acute or chronic angleclosure glaucoma, due to increased thickness of the peripheral cornea than with pupillary block

Nail-Patella Syndrome• dysplasia of the nails and absent or hypoplastic

patella as cardinal features, has been associated with open-angle glaucoma.

Oculodentodigital Dysplasia• hypoplastic dental enamel, microdontia, bilateral

syndactyly, and a characteristic thin nose. • Glaucoma: mild developmental abnormalities of the

anterior chamber angle• autosomal dominant mutation in the connexin-43

gene (CJA1, gene locus 6q21)

Prader-Willi Syndrome• Muscular hypotonia, hypogonadism, obesity, and mental

retardation• Abnormality of chromosome 15. • Ocular findings: oculocutaneous albinism and congenital ectropion

uveae, which may be associated with open-angle glaucoma

Rubinstein-Taybi Syndrome• mental and motor retardation • typical congenital skeletal deformities with characteristically large,

broad thumbs and first toes• Ocular findings: bushy brows, hypertelorism, epicanthus,

antimongoloid slant of eyelids, and hyperopia,Infantile or juvenile glaucoma(open angle)

• autosomal dominant

Stickler Syndrome • Hereditary progressive arthroophthalmopathy• An autosomal dominant connective tissue dysplasia, • Characterized by ocular, orofacial, and generalized

skeletal abnormalities • Ocular manifestations :o High myopiao Open-angle glaucomao Cataractso Vitreoretinal degeneration, o Retinal detachment o Numerous iris processes, suggestive of a developmental

abnormality of the angle neovascular glaucoma

• Three forms of Stickler syndrome 1. Type I :mutation in the COL2A1 gene 2. Type II :mutation in the a1-polypeptide of collagen

XI (COL11A1)3. Type III :mutations in the collagen, type XI, alpha 2

gene (COL11A2)

• Wagner syndrome :mutation in the gene encoding chondroitin sulfate proteoglycan-2 (CSPG2) a proteoglycan found in the vitreous

• Marshall syndrome: mutations in the COL11A1 gene

• Weissengacher-Zweymuller syndrome :o also called Pierre Robin syndrome o fetal chondrodysplasia mutation in the

COL11A2 gene (as in Stickler syndrome type III).

Waardenburg Syndrome• autosomal dominant disorder • lateral displacement of the medial canthi;• hyperplasia of the medial brows; • a prominent, broad root of the nose; • sectorial or complete iris heterochromia; • congenital deafness and a white forelock • defect of neural crest-derived tissues and is caused

by a mutation in the PAX3 gene (gene map locus 2q35,

• Open-angle glaucoma

Walker-Warburg Syndrome• Hydrocephalus (H)• Agyria (A)• Retinal Dysplasia (RD)• With or without Encephalocele (±E),• Multiple eye abnormalities have been reported, including congenital glaucoma

Cockayne Syndrome• Autosomal recessive disorder• Characterized by dwarfism and birdlike facies. • Ocular manifestations • “salt and pepper” retinopathy • Cataracts• Corneal ulcers or opacities• Nystagmus• Hypoplastic irides• Irregular pupils