Pediatric glaucoma terminology

RESEARCH REVIEW

Pediatric Glaucoma TerminologyAnuradha Ganesh,1,2 Dang Tam Mai,1,3 and Alex V. Levin1,4*1Pediatric Ophthalmology and Ocular Genetics, Wills Eye Institute, Philadelphia, Pennsylvania2Department of Ophthalmology, Sultan Qaboos University Hospital, Muscat, Oman3Department of Glaucoma, Ho Chi Minh City Eye Hospital, Saigon, Viet Nam4Thomas Jefferson University, Philadelphia, Pennsylvania

Received 30 June 2011; Accepted 23 November 2011

Glaucoma is a term that refers to many different disorders which

may be characterized by age of onset, associated ocular findings,

or associated systemic malformations and diseases. Specification

of the type of glaucoma, both clinically, and where applicable,

molecularly aids in diagnosis, counseling, treatment, and prog-

nosis. The objective of this report is to assist geneticists in

understanding glaucoma and recognizing the importance of

detailed terminology in clinical genetic diagnosis.

� 2013 Wiley Periodicals, Inc.

Key words: pediatric glaucoma; classification; terminology;

genetics

INTRODUCTIONGeneticists will frequently be involved with the care of patients with

genetic forms of glaucoma, either in isolation or as part of ocular or

systemic syndromes. Strategies for molecular genetic diagnostic

testing and genetic counseling require a clear understanding of the

phenotype and applicable medical literature. Standardized descrip-

tion and definition of human phenotypic variations also facilitates

reliable comparisons of findings among patients. Much of the

terminology required for a clear understanding is provided by

ophthalmologist consultation or found in the ophthalmic litera-

ture. The geneticist usually does not have the tools to identify the

ocular phenotype. The purpose of this study is to familiarize the

geneticist with pediatric glaucoma and the ophthalmic terminology

used in the phenotypic characterization required for analysis and

understanding. This is particularly relevant in the context of the

recent emphasis in medical genetics on phenotypic analysis and the

importance of using the same phenotypic language [Allanson et al.,

2009].

Glaucoma is the term used to describe a disorder of the optic

nerve (an optic neuropathy) characterized by a distinct type of

damage, typically consequent to elevated pressure inside the eye.

Without early detection and proper treatment, this disorder can

lead to severe irreversible vision loss and total blindness. It is

predicted that by 2020, 79.6 million people worldwide will have

glaucoma, 11.2 million of whom will be bilaterally blind. In the

United States, the number is between 100,000 and 200,000 blind

individuals [Quigley and Broman, 2006]. Glaucoma is considered

as the second leading cause of blindness worldwide [Resnikoff et al.,

2004].

The exact mechanism by which elevated pressure in the eye

occurs is multifactorial and in part defines the type of glaucoma.

Genetic factors play a major role in contributing to glaucoma risk

and pathogenesis. Although the ultimate death of optic nerve

neurons occurs by apoptosis, the biochemical pathophysiology

that causes elevated pressure to induce the apoptotic pathway is

largely not understood [Farkas and Grosskreutz, 2001]. Particularly

in the elderly, and in normal tension glaucoma, where optic nerve

damage occurs in the setting of normal eye pressures [Cheng et al.,

2009], vascular factors at the level of the blood supply to the optic

nerve may also have some importance.

In this review, we briefly discuss the embryology and genetics of

anterior segment development relevant to glaucoma, and present

the clinical and molecular classification of various pediatric glau-

coma entities.

ANATOMY OF THE EYE RELEVANT TO GLAUCOMA

Light which enters the eye is focused by the cornea and lens onto the

retina where a chemical process (phototransduction) converts the

light into electrical images that are ultimately carried to the brain via

nerve fibers that pass from the retinal surface through the optic

nerve head (Fig. 1) to the brain. The major vasculature of the retina,

the central retinal artery and vein, travel to the eye within the

Grant sponsor: Foerderer Fund.

*Correspondence to:

Alex V. Levin, M.D., MHSc, Chief, Pediatric Ophthalmology and Ocular

Genetics, Wills Eye Institute, 840 Walnut Street, Suite 1210, Philadelphia,

PA 19107-5109. E-mail: [email protected]

Article first published online in Wiley Online Library

(wileyonlinelibrary.com): 18 September 2013.

DOI 10.1002/ajmg.a.35205

How to Cite this Article:Ganesh A, Mai DT, Levin AV. 2013. Pediatric

glaucoma terminology.

Am J Med Genet Part A 161A:3205–3215.

� 2013 Wiley Periodicals, Inc. 3205

anterior optic nerve and then fan out into branches which travel

along the retinal surface in all quadrants. The central retinal artery

and vein appear in the eye at the center of the optic nerve within a

depression or cavity called the optic nerve cup. As nerve cells are lost

as a result of glaucoma, the cup enlarges (Fig. 1).

The anterior segment of the eye includes all structures lying in

front of the vitreous and includes the cornea, iris, ciliary body,

anterior chamber, and lens (Fig. 2). The ocular abnormalities

underlying glaucoma primarily involve the angle of the anterior

chamber which contains the outflow pathways: trabecular mesh-

work, Schlemm’s canal, and episcleral veins (Fig. 2). Glaucoma

results when the fluid of the eye cannot escape through these

drainage pathways at the same pace with which the intraocular

fluid (aqueous humor) is made.

The ciliary body is the tissue located for 360� just behind the

peripheral iris, out of view to the examiner. It can only be viewed

using ultrasound techniques or special lenses applied to the surface

of the eye (Fig. 2). The ciliary body is lined with epithelium (ciliary

epithelium) which produces the aqueous humor that flows forward,

in front of the lens and through the pupil to fill the anterior chamber:

the space between the iris and the overlying vaulted crystal clear

cornea (Fig. 2). The aqueous humor nourishes and inflates the

anterior part of the eye. This fluid is produced continuously

throughout the day and therefore must drain continuously.

Drainage is achieved via the trabecular meshwork located at the

peripheral edge of the iris for 360� (Fig. 3). This is both a structural

and cellular filter for the aqueous humor outflow. The trabecular

meshwork function is regulated by cellular function, in particular

the production of glycosaminoglycans and other related substances.

Once fluid passes through the trabecular meshwork, it enters

Schlemm’s canal, a passageway buried within the sclera for 360�

just beyond the edges of the cornea. Fluid is then dispersed into the

episcleral veins.

The terms open angle and closed angle glaucoma are more often

used in the setting of adult glaucoma. In both types of glaucoma,

there is a ‘‘backup’’ of fluid and increased pressure in the eye which

damages the optic nerve. In closed angle glaucoma, the peripheral iris

is too anterior and physically blocks the trabecular meshwork.

This form of glaucoma is uncommon in children and rarely

described as a primary malformation. Rather, it is usually secondary

to something pushing the iris forward from behind, such as

FIG. 1. Composite photograph showing (A) normal optic nerve head (arrows delineate optic nerve cup) and (B) optic nerve head in glaucoma (arrows

delineate optic nerve cup enlarged due to glaucoma-induced damage).

FIG. 2. Schematic representation of trabecular meshwork and

drainage angle of the anterior segment of the eye. Red arrow

indicates pathway of aqueous humor production and exit. Ocular

abnormalities underlying glaucoma primarily involve the angle of

the anterior chamber which contains the outflow pathways:

trabecular meshwork, Schlemm’s canal, and episcleral veins. The

ciliary body is the tissue located for 360� just behind the

peripheral iris, out of view to the examiner. It can only be viewed

using ultrasound techniques or special lenses applied to the

surface of the eye. The ciliary body is lined with epithelium (ciliary

epithelium) which produces the aqueous humor that flows

forward, in front of the lens and through the pupil to fill the anterior

chamber: the space between the iris and the overlying vaulted

crystal clear cornea. (Figure by Dinh Khai Tran.)

3206 AMERICAN JOURNAL OF MEDICAL GENETICS PART A

microspherophakia (isolated or in Weill–Marchesani syndrome),

ectopia lentis, retinoblastoma, or retinal disorders, such as retin-

opathy of prematurity. The minimal residual iris in aniridia can

turn up and cause another form of angle closure. Almost all other

forms of pediatric glaucoma are considered open angle: there is

no physical obstruction by the iris of the trabecular meshwork.

The resistance to outflow in open angle glaucoma usually lies in

the trabecular meshwork (goniodysgenesis) or Schlemm’s canal.

Aqueous outflow may also become obstructed due to elevated

episcleral venous pressure secondary to conditions, such as

Sturge–Weber syndrome.

CLINICAL SIGNS OF GLAUCOMA

The clinical signs of glaucoma vary greatly between different types

of glaucoma and different ages.

BuphthalmosIn newborns, congenital glaucoma may present with an enlarged

eyeball, termed buphthalmos (ox eye; Fig. 4). This is the result of

high intraocular pressure (IOP) prenatally which leads to stretching

of the eye. In infantile glaucoma, the signs may have a more subtle

onset. The eye can enlarge in response to elevated IOP until at least

2- to 3-year old and sometimes up to 5-year old.

CorneaA horizontal corneal diameter >12 mm should raise suspicion of

glaucoma along with other signs of progressive buphthalmos which

include increasing myopia (nearsightedness) or non-physiologic

loss of hyperopia (farsightedness) as measured by an ophthalmol-

ogist. The ophthalmologist can view the cornea with magnification

(slit lamp biomicroscopy) to reveal breaks in one of the layers of the

inner cornea, Descemet’s membrane. These breaks called Haab stria

are due to the stretching effect of the increased IOP on the cornea

(Fig. 5). In another type of glaucoma called juvenile glaucoma,

corneal enlargement is not as prominent, but progressive myopia or

loss of previous hyperopia due to globe enlargement may occur.

The high IOP also causes the cornea to become edematous.

Clinically this appears as a cloudy cornea limiting the view of the

underlying pupil and iris. This edema may be superficial (epithelial

edema) or deeper in the cornea (stromal edema). The latter is more

concerning as it takes longer to resolve and reflects longer standing

glaucoma, particularly in congenital glaucoma. The edema results

FIG. 3. Trabecular meshwork of a child with congenital glaucoma.

Short arrows indicate anterior trabecular meshwork. Long arrows

indicate anteriorly positioned iris. I, iris; P, pupil. Cornea is not

visible due to lens used to create this image but it is at the top of

the photo (C).

FIG. 4. Primary congenital glaucoma with buphthalmus and cloudy

cornea.

FIG. 5. Haab stria in a child with infantile glaucoma. Opposing arrows

indicate the edges of the stria.

GANESH ET AL. 3207

in epiphora and photophobia. Older children with juvenile

glaucoma tend not to get corneal edema unless the IOP is extra-

ordinarily and acutely high.

Optic NerveAt all ages, progressive enlargement of optic nerve cup, referred to as

cupping, is also a sign of glaucoma. In older children where other

signs of glaucoma, such as an enlarged eye or cloudy cornea, are

usually absent it may not be till visual loss occurs that the patient

visits an eye doctor, at which point the glaucoma is by definition

often so far progressed, and the optic nerve cup so enlarged, that

intervention is unlikely to be restorative and the prognosis dra-

matically reduced. This makes it very important to periodically

screen at risk children for symptoms and signs of glaucoma (Tables I

and II). Optic nerve cupping is assessed by comparative serial

examination and photography which is assisted by the use of

various tools to measure the thickness of the nerve fiber layer of

the retina as it feeds into the nerve (e.g., optical coherence tomog-

raphy, OCT). The size of the cup is often described as a percentage of

the entire disk surface. For example a 0.3 cup occupies 30% of the

optic nerve head surface. Cups in excess of 0.5–0.6 are concerning.

In children less than 5 years, an enlarged cup may reduce in size with

successful treatment.

Visual FieldThe result of the optic nerve damage in glaucoma is initially

visual field loss mainly in the peripheral vision, but it can progress

to total vision loss at the end stage of the disease. The visual field is

clinically assessed by perimetry measuring the ability of the subject

to distinguish stimulus light from background illumination.

Unfortunately children are usually unable to perform perimetry

reliably until late in the first decade of life at the earliest.

Intraocular PressureMeasurement of eye pressure (tonometry) requires the child to be

completely compliant, still, and calm. In younger children at risk for

glaucoma, this may require an examination under anesthesia or

sedation. There are two methods to determine the IOP: contact and

non-contact. In the contact method, an anesthetized ocular surface

is mandatory. The tonometer lightly indents (applanation) the

surface of the cornea. The resistance to this deformation is meas-

ured by the tonometer. With non-contact methods, a brief air puff

of pressurized air is used. It senses deflection of the cornea in

reaction to the puff. It still requires some patient cooperation.

Usually, IOP in normal infants is from 11 to 14 mmHg. Similar to

normal adults, the mean IOP in normal older children is approx-

imately 16 mmHg. IOP is classically highest in the morning and

varies throughout the day. When IOP is greater than 20 mmHg at

any point in a calm, resting infant or there is an asymmetry of more

than 5 mmHg between both eyes, it is a suspicious sign of glaucoma.

TABLE I. Ocular Risk Factors for Pediatric Glaucoma

Family history of pediatric glaucoma or glaucoma under40-year-old

Ocular anomaliesPeters anomalyAxenfeld–Rieger spectrumIridogoniodysgenesisIris hypoplasiaAniridiaCongenital ectropion uveaMicrospherophakiaEctopia lentisPrimary aphakiaPersistent fetal vasculatureNanophthalmos

Previous ocular trauma or intraocular surgeryEspecially aphakia following lensectomy for pediatric cataract

Steroid useIntraocular infectionUveitisIntraocular tumors

RetinoblastomaJuvenile xanthogranuloma

Total retinal detachment or non-attachment in infancy

TABLE II. Syndromes With Childhood Glaucoma

Cornelia de Lange syndromeCockayne syndromeCongenital rubellaCutis marmorata telengiectasia congenitaCystinosisEpidermal nevus syndromeGlaucoma with microcornea and absent sinusHepatocerebrorenal syndrome (Zellweger)Infantile glaucoma with retardation and paralysisKniest syndrome (skeletal dysplasia)Lowe syndromeMarfan syndromeMucopolysaccharidosisNail patella syndromeNeurofibromatosis type 1 with orbital involvementOculodermal melanocytosis (nevus of Ota)Oculodentodigital dysplasiaPhakomatosis pigmentovascularis type IIbRefsum syndromeRobinow syndromeRubinstein–Taybi syndromeSHORT syndromeStickler syndromeSturge–Weber syndromeWarburg syndromeWolf–Hirschhorn (4p-) syndrome8q23.3 deletion9p deletion syndromeTrisomy 13Trisomy 21


Interpretation of the IOP measurement must be linked to other

signs of the disorder. IOP should not be measured while a child cries

or the eyelids are held with effort, because it will result in a falsely

high IOP. There are other factors which can affect the accuracy of

tonometry including the central corneal thickness (CCT, also known

as pachymetry), measured by a corneal pachymeter, and the stiffness

of the corneal (e.g., a scarred cornea is stiffer).

ANTERIOR SEGMENT DEVELOPMENT

Anterior segment development involves surface ectoderm (lens and

corneal epithelium), neuroectoderm (posterior epithelium of the

iris and ciliary body, sphincter, and dilator muscle of the iris) and

neural crest (corneal stroma and endothelium, iris and ciliary body

stroma, trabecular meshwork and Schlemm’s canal), and is

controlled by a complex molecular genetic network involving

multiple signals, their receptors and transcription factors [Gould

et al., 2004]. Mutations in developmental genes lead to anterior

segment dysgenesis and contribute to the pathogenesis of pediatric

glaucoma. Abnormal development may affect the function of the

drainage structures without disturbing morphology.

Ocular development begins with the formation of the optic

vesicle from the neuroectoderm largely under the influence of

Sonic hedgehog (SSH, OMIM #606778) and PAX2 (OMIM

#167409), and PAX6 (OMIM #607108). The growing optic vesicle

forms the optic cup and interacts with the overlying surface

ectoderm to induce formation of the lens placode. By the 7th

week of intrauterine life, the latter has given rise to the lens through

a process of proliferation, differentiation, invagination, and detach-

ment. Neural crest cells migrate between the lens and the surface

ectoderm (future corneal epithelium) and give rise to the remainder

of the cornea, iris, and drainage structures.

Cell signaling plays an important role in cell proliferation

and differentiation. Known ocular developmental transcription

factors include PAX6, FOXC1 (OMIM #601090), FOXC2

(OMIM #602402), PITX2 (OMIM *601542), PITX3 (OMIM

þ602669), LMX1B (OMIM *602575), FOXE3 (OMIM *601094),

LTPB2 (OMIM *602091), and CYP1B1 (OMIM *601771). Precise

levels of transcription factor activity are required in the progenitor

cells that give rise anterior segment structures. Both hypomorphic

and overexpressed alleles can lead to malformation.

CLASSIFICATION SYSTEM FOR PEDIATRIC GLAUCOMA

Pediatric glaucoma can be categorized based on the etiology, age of

onset of the condition, and associated ocular and systemic findings, as

primary glaucoma, glaucoma with associated syndromes, and sec-

ondary glaucoma [Ho and Walton, 2004; Yeung and Walton, 2010].

Advances in the past decade have allowed an enriched understanding

of the molecular genetics of glaucoma resulting in new terminology.

The symbol GLC is used to identify primary glaucoma loci. A number

that refers to the type of primary glaucoma is then added: GLC1 for

open angle glaucoma, GLC2 for angle closure glaucoma, and GLC3

for congenital or infantile glaucoma. GLC1 includes both adult onset

primary glaucomas(classic primary open angleglaucoma and normal

tension glaucoma) as well as juvenile open angle glaucoma (JOAG). A

capital letter is then added torepresent the order in which the loci were

discovered. The GLC1 glaucomas are summarized in Table III. No

gene locus has been discovered for GLC2. The GLC3 glaucomas are

summarized in Table IV.

TABLE III. Genetic Classification for Primary Open Angle Glaucoma and Closed Angle Glaucoma

Phenotype Locus GeneChromosomal

location InheritancePOAG/JOAG Juvenile or adult onset GLC1A MYOC (formerly TIGR) 1q24.3-q.25.2 AD complexPOAG adult onset, most often

NTG after age 40GLC1B 2cen-q13 AD

POAG adult onset; moderate responseto IOP-lowering medications

GLC1C 3q21-q24 AD

POAG adult onset, high IOP GLC1D 8q23 ADPOAG adult onset, NTG GLC1E OPTN 10p14-p15 ADPOAG adult onset GLC1F 7q35-36 ADPOAG adult onset, high or low IOP GLC1G WDR36 5q21.3-q22.1 AD complexPOAG adult onset GLC1H 2p15-p16 ADPOAG earlier adult onset GLC1I 15q11-q13 ComplexPOAG (JOAG) juvenile onset GLC1J 9q22 ADPOAG (JOAG) juvenile onset GLC1K 20p12 ADPOAG adult onset, NTG GLC1L 3p22-p213p ComplexPOAG (JOAG) juvenile onset GLC1M 5q22.1-q32 ADPOAG (JOAG) juvenile onset GLC1N 15q22-q24 ADPOAG (JOAG) NTG GLC1O NTF4 19q13.3 ComplexPACG GLC2 Not identified

POAG, primary open angle glaucoma; JOAG, juvenile open angle glaucoma; AD, autosomal dominant; IOP, intraocular pressure; NTG, normal tension glaucoma; PACG, primary angle closure glaucoma.

GANESH ET AL. 3209

Primary GlaucomaPrimary pediatric glaucomas are those resulting from an isolated

intrinsic structure abnormality of the aqueous outflow pathway

(trabeculodysgenesis) with no other associated abnormalities of the

eye or body. The origin of these diseases is genetic. They can be sub-

classified based on age of onset into two subgroups.

Primary congenital/infantile glaucoma. When presenting at

birth the disease is termed newborn or congenital glaucoma.

Infantile primary glaucoma is the term used when the disease is

not clinically evident at birth, and appears any time from birth up to

4-year old. Typical symptoms and signs are described above. The

angle is open but the trabecular meshwork visibly abnormal on

gonioscopy.

Primary congenital/infantile glaucoma is linked to several loci.

The cytochrome P450 gene (CYP1B1, GLC3A, 2p21, OMIM

#231300) is mutated in a large proportion of cases, particularly

in the Middle East [Sarfarazi et al., 1995; Stoilov et al., 1997] GLC3B

(OMIM %600975) at 1p36.2-p36.1 [Akarsu et al., 1996], GLC3C

(OMIM %613085) at 14q24.3 [Stoilov and Sarfarazi, 2002], and

GLC3D (OMIM #613086) at 14q24.2-q24.3 [Firasat et al., 2008] are

also associated with primary congenital/infantile glaucoma. LTBP2

has been identified as the mutated gene of GLC3D [Ali et al., 2009].

Primary congenital/infantile glaucoma is typically autosomal

recessive. Rarely, non-penetrance and vertical transmission is

observed creating a pattern of pseudo-dominance [Panicker

et al., 2002]. Some authors have suggested a role for the MYOC

gene (OMIM *601652) via digenic interactions [Kaur et al., 2005].

Primary juvenile open angle glaucoma (JOAG). The disorder

is recognized between 4 and 40 years old. Buphthalmos does not

occur and the patient usually has a normal angle appearance on

gonioscopy. A severe elevation of eye pressure is noted in many

affected patients and vision loss tends to be substantial if unrecog-

nized and untreated [Wiggs et al., 1995, 1996]. JOAG is an

autosomal dominant disorder with well-recognized variability of

expression, in particular with regard to age of onset. One locus for

JOAG has been mapped to human chromosome lq21-q31 (GLC1A,

OMIM #137750 [Sheffield et al., 1993]). Mutations in the myocilin

gene at this locus are highly penetrant. Other loci for JOAG have

been mapped, but no genes have been identified to date (Table III)

[Wiggs et al., 2004; Wang et al., 2006; Fan et al., 2007; Pasutto et al.,

2009].

Glaucomas Associated With Ocular Anomalies orSystemic SyndromesGlaucoma may be associated with the ocular anomalies or systemic

syndromes (Tables I, II, and V).

Associated with ocular anomalies. Malformations of the ante-

rior segment, with the exception of iris coloboma, are usually

associated with glaucoma due to associated goniodysgenesis. These

disorders are collectively referred to as anterior segment dysgenesis.

These disorders represent a phenotypic spectrum characterized by

genetic and phenotypic heterogeneity as well as marked intra- and

interfamilial variable expressivity. In some cases this has been

attributed to variations in gene dosage [Sowden, 2007]. For exam-

ple, mutations in PITX2 may result not only in the Axenfeld–Rieger

spectrum [Semina et al., 1996], but have also been associated with

autosomal dominant iris hypoplasia [Heon et al., 1995], iridogo-

niodysgenesis [Kulak et al., 1998], and Peters anomaly [Doward

TABLE V. Genetics of Pediatric Glaucoma Associated With Ocular Anomalies

Anomaly Locus Gene Chromosomal location Inheritance*Peters anomaly AN PAX6 11p13 AD

RIEG1 PITX2 4q25-q26 ADRIEG3 FOXC1 6p25 ADGLC3A CYP1B1 2p21-p22 AR

Axenfeld–Rieger spectrum/iridogoniodysgeneis RIEG1/IRID2 PITX2 4q25-q26 ADAxenfeld–Rieger spectrum/iridogoniodysgenesis IGDA/IRID1/RIEG3 FOXC1/FKHL7 6p25 ADAniridia AN PAX6 11p13 ADAxenfeld–Reiger spectrum RIEG2 Not identified 13q14 ADPrimary aphakia FOXE3 1p33 ARNanophthalmos NNO1 11p ADNanophthalmos NNO2 MFRP 11q23 ADNanophthalmos NNO3 2q11-q14 AD

*AD, autosomal dominant; AR, autosomal recessive.

TABLE IV. Genetic Classification for Primary Congenital/Infantile

Glaucoma

LocusChromosomal

location Gene InheritanceGLC3A 2p21-p22 CYP1B1 AR complexGLC3B 1p36.1-p36.2 ARGLC3C 14q24.3-q31.1 ARGLC3D 14q24.2-24.3 LTBP2 AR

AR, autosomal recessive.


et al., 1999]. Most of the conditions involve structures derived from

the neural crest.

Peters anomaly (OMIM #604229). Peters anomaly is charac-

terized by central corneal scarring and iridocorneal adhesions with

or without cataract or attachment of the lens to the back of the

cornea (Fig. 6). This is a malformation sequence in which incom-

plete ‘‘pinching off’’ of surface ectoderm to form the embryonic lens

results in an inability for normal neural crest migration to occur.

Eighty percent of cases are bilateral. Glaucoma occurs in 50% of

patients. It is associated with other ocular anomalies including

microphthalmia in 50% of patients. Approximately 60% patients

present with systemic anomalies [Heon et al., 1992]. Peters anomaly

is part of the Krause–Kivlin or Peters-plus syndrome (OMIM

#261540) [van Schooneveld et al., 1984; Kivlin et al., 1986].

Mutations in the PAX6 [Hanson et al., 1994], PITX2 [Doward

et al., 1999], FOXC1 [Honkanen et al., 2003], and CYP1B1 [Vincent

et al., 2001; Edward et al., 2004] genes each have been reported in

patients with Peters anomaly. Peters anomaly may be seen in

association with Axenfeld–Rieger syndrome and aniridia

[Honkanen et al., 2003; Sawada et al., 2011]. Peters-plus syndrome

can be caused by mutations in the B3GALTL gene (13q12.3)

[Hennekam et al., 1993; Lesnik Oberstein et al., 2006].

Axenfeld–Rieger spectrum (OMIM #602482). The term

Axenfeld–Rieger spectrum replaced the previous terms Axenfeld

anomaly, Axenfeld syndrome, Rieger anomaly, and the Rieger

syndrome as molecular genetics has made clear that the former

terms were simply descriptors of the variable expression of a

disorder with common etiology [Walter et al., 1996; Alward,

2000]. Axenfeld–Rieger is an autosomal dominant disorder char-

acterized by varying degrees of iris malformation, corectopia

(displacement of the pupil), polycoria (multiple pupils), peripheral

irido-corneal strands, and, most importantly, posterior embryo-

toxon (Fig. 7) [Idrees et al., 2006]. Posterior embryotoxon (also

known as an anterior displacement of Schwalbe’s line) refers to

anteriorized peripheral termination of the inner layer of the cornea

(Descemet membrane) often with strands of iris attached to it. This

can only be recognized by slit lamp examination and sometimes

gonioscopy (an ophthalmic examination technique at the slit lamp

using a lens placed on the eye to see the far peripheral iris and

drainage angle). Posterior embryotoxon may occur as an isolated

minor malformation with no consequence, and in other disorders

(e.g., Alagille syndrome), but is almost a sine qua non for

Axenfeld–Rieger.

Approximately 50% of patients with Axenfeld–Rieger develop

secondary glaucoma, which may present at birth or not until

adulthood [Shields et al., 1985]. Systemic features may include

mild facial dysmorphism, dental anomalies, redundant periumbil-

ical skin, hypospadias in males, and growth retardation. These

system features in combination with Axenfeld–Rieger spectrum

comprised what has traditionally been called ‘‘Rieger syndrome.’’

Three genetic loci have been associated with Axenfeld–Rieger

spectrum: 4q25 (PITX2) [Murray et al., 1992; Semina et al., 1996],

6p25 (FOXC1) [Nishimura et al., 1998], and 13q14 (gene not

identified) [Phillips et al., 1996].

Iris hypoplasia/Iridogoniodysgenesis/(OMIM #601631, 601542).

This is characterized by a smooth appearance of the iris, and absent

crypts. The iris is slate-gray or brown in color, with a poorly

developed stroma, and the iris collarette is absent or small and

peripheral. As a result the pupillary sphincter looks very prominent

like a ring (Fig. 8). When iris hypoplasia is associated with abnormal

angle structure and glaucoma, the condition is termed as iridogo-

niodysgenesis (IRID1) [Jerndal, 1972]. However the angle may

look normal on gonioscopy and there has been a suggestion to

replace the term iridogoniodysgenesis with iris hypoplasia [Idrees

et al., 2006]. Iridogoniodysgenesis associated with systemic

features (similar to those found in Axenfeld–Rieger syndrome),

is categorized as iridogoniodysgenesis syndrome (IRID2). Familial

iridogoniodysplasia is a term that has been described a form of

open-angle glaucoma in which developmental anomalies of the iris

and irido-corneal angle are associated with glaucoma [Jordan et al.,

FIG. 6. Peters anomaly is characterized by central corneal scarring

and iridocorneal adhesions with or without cataract or attachment

of the lens to the back of the cornea. (Abnormal pupil due to

surgery.)

FIG. 7. Axenfeld–Reiger spectrum. Arrows indicate posterior

embryotoxon: an anteriorized connection between the peripheral

iris and the inner surface of the cornea. Note also irregular pupil

(not perfectly round) and areas of anterior iris stromal atrophy (*).

GANESH ET AL. 3211

1997]. However, we think that this entity is the same as iris

hypoplasia/iridiogoniodysgenesis.

IRID1 and IRID2 are autosomal dominantly inherited and

caused by mutations in FOXC [Lehmann et al., 2002] and

PITX2 [Heon et al., 1995; Alward et al., 1998; Nishimura et al.,

2001], respectively.

Aniridia (OMIM #106210). Despite its name which accurately

describes the near absence of iris (Fig. 9), aniridia is a panocular

malformation. Additional ocular anomalies may include abnormal

vascularization of the corneal (pannus), cataract, nystagmus, optic

nerve hypoplasia, and underdevelopment of that part of the retina

normally designed for straight ahead vision (macular or foveal

hypoplasia) [Nelson et al., 1984]. Glaucoma may result from

goniodysgenesis, progressive blocking of the trabecular meshwork

by the residual iris or aplasia of Schlemm’s canal.

Aniridia is an autosomal dominant disorder with high penetrance

and variable expression, usually due to heterozygous mutations in

the PAX6 gene or as part of the WAGR (Wilms tumor, aniririda,

genital anomalies, and retardation) syndrome due to contiguous

deletion at 11p13 involving PAX6 and WT1 (Wilms tumor) gene

[van Heyningen et al., 2007].

Congenital ectropion uveae. Congenital ectropion uveae is a rare,

non-progressive anomaly characterized by the presence of iris

pigment epithelium, which is normally confined to the back surface

of the iris on the anterior surface of the iris stroma (Fig. 10). It is

usually unilateral and non-heritable. Rare systemic associations

have been reported (e.g., neurofibromatosis type 1) [Ritch et al.,

1984; Mandal, 1999; Harasymowycz et al., 2006]. Many studies have

documented a relationship between the presence of ectropion uveae

and the eventual development of glaucoma [Ritch et al., 1984;

Dowling et al., 1985; Mandal, 1999].

Primary aphakia (OMIM #610256). Primary aphakia (congenital

absence of the lens) arises due to the early developmental arrest of

the lens placode, and is usually associated with severe deformities of

the eye including anterior segment malformations, corneal opaci-

fication, glaucoma due to goniodysgenesis, and retinal dysplasia. It

may be caused by mutations in the FOXE3 gene (1p33) [Valleix

et al., 2006]. The association of abnormalities of structures arising

from the neural crest cells with primary aphakia can be attributed to

the inductive effect of anterior lens epithelium on anterior segment

development [Idrees et al., 2006; Sowden, 2007].

Nanophthalmos. Nanophthalmos is a developmental disorder

of the eye in which the eye is reduced in size, but is otherwise

structurally normal. It is characterized by marked farsightedness

(hyperopia), decreased axial length, and shallow anterior chambers.

The sclera is thickened which is the distinguishing feature from

simple microphthalmia. Glaucoma may occur due to crowding

of the anterior chamber angle [Kimbrough et al., 1979]. Two loci

FIG. 8. Iris hypoplasia. The iris is slate-gray or brown in color, with a

poorly developed stroma, and the iris collarette is absent or small

and peripheral. As a result the pupillary sphincter looks very

prominent like a ring.

FIG. 9. Aniridia. Note absence of iris and pupil. Arrows indicate edge

of lens which is ectopic mildly in the upward direction and to the

right. Bright circular light reflex from camera overlies gray cataract

in lens.

FIG. 10. Congenital ectropion uveae is a rare, non-progressive

anomaly characterized by the presence of iris pigment epithelium,

which is normally confined to the back surface of the iris on the

anterior surface of the iris stroma. (Semicircular black area at top

of iris is a post-surgical change.)


for autosomal dominant nanophthalmos (NNO1) have been

mapped to 11p (OMIM %600165) [Othman et al., 1998], and

2q11-q14(NNO3; OMIM %611897) [Li et al., 2008]. Autosomal

recessive nanophthalmos (NNO2; OMIM #609549) can be caused

by mutation in the MFRP gene (11q23).

Glaucoma associated with systemic syndromes. There are a

wide variety of syndromes with which glaucoma may occur, usually

through goniodysgenesis (Table II) [Yeung and Walton, 2010].

Other factors may also be involved. In Sturge–Weber syndrome,

when glaucoma presents early in life, it is likely to be the result of

goniodysgenesis, similar to primary congenital/infantile glaucoma.

Later in childhood, glaucoma results from an elevated episcleral

venous pressure due to hyperplasia of episcleral vessels. In some

syndromes, such as neurofibromatosis, mucopolysaccharidosis, or

cystinosis, there may be deposition or other forms of physical

obstruction in the trabecular meshwork which obstruct the outflow

of aqueous and impair drainage of aqueous. In syndromes asso-

ciated with ectopia lentis (e.g., homocytinuria) or retinal non-

attachment (e.g., Walker–Warburg)/detachment (e.g., Stickler),

the iris may be caused to move forward and create a physical

obstruction to the trabecular meshwork (i.e., closed angle

glaucoma).

Secondary (Acquired) GlaucomaGlaucoma occurring secondary to eye injury, inflammation, infec-

tion, tumor, lens, or certain drugs, such as steroids, is called

secondary glaucoma (Table I).

CONCLUSION

Knowledge of the terminology used by ophthalmologists in the

description of children with glaucoma may be useful to geneticists

for the purpose of counseling, syndrome identification, and molec-

ular genetic testing. There are many forms of pediatric glaucoma.

Clinical classification is based on the etiology, age of onset, and

presence of associated ocular or systemic abnormalities. With

ongoing discovery of underlying genetic causes of pediatric glau-

coma, classification has been reorganized to reflect the underlying

genetic alteration and phenotypic changes. Both genotypic and

phenotypic heterogeneity are well recognized.

ACKNOWLEDGMENTS

This study was supported in part by the Foerderer Fund.

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