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INTRODUCTION

Primary congenital glaucoma (Mendelian Inheritance in Man [MIM] #231300, %600975, %613085, #613086) is an isolated abnormality of the anterior chamber drain-age angle (goniodysgenesis) that causes increased intraocular pressure (IOP) and is not associated with systemic disease or other ocular malformation.1 The most common identifiable cause worldwide is reces-sive CYP1B1 mutations (MIM] *601771), especially in certain consanguineous populations.2 In 2009 recessive mutations in a second gene - LTBP2 (MIM *602091)− were identified in Pakistani, gypsy, and Iranian children who were diagnosed with primary congenital glaucoma.3, 4 Primary congenital glaucoma can be clinically classified into three subtypes: “pri-mary newborn glaucoma” when obvious at birth, “primary infantile glaucoma” when recognized from 1 month to 2 years of life, and “juvenile primary con-genital glaucoma” evident after 2 years of life.1

Developmental glaucoma broadly refers to conditions of abnormal angle development which may be associated with non-ocular and/or other ocular disease. Developmental glaucoma can be

from heterozygous mutation in anterior segment developmental genes such as PAX6 (MIM *607108), FOXC1 (MIM *601090), and PITX2 (MIM *601542). The glaucoma in these dominant conditions is usu-ally associated with iris developmental abnormalities (iridiogoniodysgenesis), can be syndromic, and is often of juvenile rather than of congenital/infantile onset although the latter can occur.5 While primary congenital glaucoma and developmental glaucoma are the most common forms of pediatric glaucoma, numerous other types exist.6

When glaucoma occurs within the first few years of life, affected children develop classic pheno-typic signs such as increased measured IOP, globe enlargement (buphthalmos) with associated myopia, Descemet membrane tears (Haab striae), corneal edema/scarring with associated astigmatism, iris atrophy, and optic nerve cupping.1 In addition, symptoms such as photophobia and increased tear-ing are common. Although the classic phenotypic signs are a consequence of increased IOP, similar signs can be part of other pediatric conditions that are sometimes mistaken as childhood glaucoma.

Ophthalmic Genetics, 32(3), 129–137, 2011© 2011 Informa Healthcare USA, Inc.ISSN: 1381-6810 print/ 1744-5094 onlineDOI: 10.3109/13816810.2010.544363

ORIGINAL ARTICLE

Conditions that can be Mistaken as Early Childhood Glaucoma

Arif O. Khan

Pediatric Ophthalmology, King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia

ABSTRACT

Primary congenital glaucoma (isolated goniodysgenesis) has classic phenotypic features such as increased measured intraocular pressure, globe enlargement (buphthalmos) with associated myo-pia, Descemet membrane tears, corneal haze/scarring with associated astigmatism, iris atrophy, and optic nerve cupping. These signs also occur in developmental glaucoma (anterior segment dysgeneses) with infantile onset. However, similar findings can occur in other pediatric conditions which are sometimes are mistaken as early childhood glaucoma.

Keywords: pediatric glaucoma, primary congenital glaucoma, buphthalmos, congenital hereditary endothelial dystrophy, infantile glaucoma, developmental glaucoma

Received 19 August 2010; revised 26 November 2010; accepted 27 November 2010

Correspondence: Dr. Arif O Khan, King Khaled Eye Specialist Hospital, Pediatric Ophthalmology, PO Box 7191, Riyadh, 11462 Saudi Arabia. E-mail: arif.khan@mssm.edu

19 August 2010

26 November 2010

27 November 2010

© 2011 Informa Healthcare USA, Inc.

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SITUATIONS WITH FALSELY INCREASED MEASURED IOP

The classic signs of early childhood glaucoma occur as a result of IOP too high for a given young eye. Thus measured IOP is often a focus of diagnosis and manage-ment in children with suspected glaucoma. Although measured IOP is important, decision-making in pediat-ric glaucoma needs to take into account other important parameters of the ophthalmic examination such as cor-neal, optic nerve, and refractive findings. This is espe-cially true because measured IOP can be falsely high (or low), particularly in children.7 These errors can be related to issues in tonomery calibration,8 tonometry method,8 patient cooperation, and/or corneal biomechanics.

Cooperation Issues

Struggling and/or eyelid squeezing during attempted IOP measurement will cause an elevated reading.7 In addition, examination under general anesthesia can result in falsely raised IOP values depending upon the agents used (eg, ketamine can increase IOP), the degree of discomfort experienced by the child during the examination (eg, from a large speculum or only partial anesthesia) and/or the degree of intrathoracic pressure from endotracheal intubation.9, 10 In general, neither the IOP measurement obtained by forceful restraint of an uncooperative child nor the IOP measurement obtained under general anesthesia should be relied upon for

decision-making regarding the diagnosis of pediatric glaucoma. For uncooperative or very young children, IOP measurement can be made while the child is sleep-ing (often after a bottle feed) or if necessary under sedation with an agent such as chloral hydrate.11

Corneal Issues

There is a relation between measured IOP and both corneal thickness and corneal hystereses.12 The role of these corneal factors in interpretation of measured IOP is evolving in adults but remains unclear for children.12,13 In adults thicker corneas tend to falsely elevate measured IOP and corneas with less hyster-esis tend to have higher measured IOP.12 These issues almost certainly come into play in measured IOP for children but exactly how to apply them practically is not known.13 A growing body of literature has documented differences in corneal thickness among different ethnicities14 and among different pediatric eye conditions such as aphakia, pseudophakia, and aniridia (MIM #106210).15 While there are no hard and fast rules, these concepts should be kept in mind when interpreting the IOP in the context of all ophthalmic data collected for a given patient. In early childhood glaucomas, central corneal thickness tends to be less than age-matched controls.15

CONDITIONS WITH GLOBE ENLARGEMENT

In children less than 2–3 years of age, increased IOP leads to globe enlargement that involves both the

FIGURE 1 (Classic signs and symptoms of early childhood glaucoma): This infant presented with classic signs of early onset glaucoma (increased intraocular pressure, buphthalmos with associated myopia, corneal haze, Haab striae, iris atrophy, and optic nerve cupping). Because of tearing she was previ-ously diagnosed with nasolacrimal duct obstruction; however, the wetness under her nose confirms a patent lacrimal system. Tearing related to photophobia is a common symptom of pedi-atric glaucoma.

FIGURE 2 (Falsely increased measured intraocular pressure): If cooperation is an issue intraocular pressure measurement should be deferred. Restraining a child to measure intraocular pressure will give falsely elevated readings.

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anterior and posterior segments (buphthalmos).1,16 Although corneal edema from increased IOP in infants is typically accompanied by buphthalmos,17 buphthal-mos from increased IOP is not always accompanied by corneal edema. Extreme buphthalmos can be associ-ated with blue sclera (from sclera thinning), lens sub-luxation (from zonular stretching/breaking), retinal detachment (from posterior segment enlargement),16 and phthisis. Milder cases often have Haab striae (described below) and a stretched limbus, with the con-junctival edge inserting onto to cornea more anteriorly than in non-buphthalmic eyes. While buphthalmos is a very useful confirmatory sign for suspected early childhood glaucoma, non-glaucomatous causes for a large-eye appearance in young children must always be kept in mind.

Megalocornea without glaucoma

Megalocornea (MIM 249300) refers to enlarged corneal size (greater than 13 mm horizontal diam-eter) with a deep anterior chamber and without concurrent vitreous chamber enlargement.18–20 Involvement is typically bilateral but can be asym-metric. Corneas are large without Descemet breaks or scarring. A stromal mosaic appearance (shagreen) can be appreciated in some cases; its absence does not rule out megalocornea but its presence is helpful in confirming the diagnosis. Another anterior seg-ment sign helpful in distinguishing megalocornea from buphthalmic changes is posterior bowing of the iris.18 This can be associated with mid and/or peripheral radial iris transillumination defects as well as evidence for pigment dispersion in later childhood. Classically (but not always) inheritance is X-linked and thus examination of the mother can be helpful in suspected cases. Two syndromes that should be considered in children with megalocornea

are Marfan (MIM #154700) and Neuhauser (MIM %249310, megalocornea-mental retardation) syn-dromes. In addition, in my experience recessive LTBP2 mutations are a rare cause of a syndrome of megalocornea and spherophakia without primary congenital/infantile glaucoma but with risk for pediatric lens–related pupillary block glaucoma and ectopia lentis (Unpublished data).

Corneal Ectasia

Isolated infantile corneal ectasia is rare and may require several visits before the diagnosis is made. Sedation may be necessary for careful slit-lamp examination; in addition, corneal topography, high frequency ultrasound, and/or anterior segment ocular coherence tomography can be helpful in con-firming the diagnosis. Corneas are thin and ectatic, can develop posterior stress lines (and even breaks that may be confused with Haab striae) with asso-ciated edema, can become globular (keratoglobus), and often confound accurate IOP measurements. Although the ectatic cornea appears large, in fact the limbal-to-limbal diameter in these cases can be normal. Corneal ectasia in young children should raise suspicion for the brittle cornea syndrome (MIM #229200), particularly when associated with blue sclera and hyperlaxity.21 The brittle cornea syndrome is a distinct bilateral entity due to recessive mutation in ZNF46922 (MIM #612078) that has been confused with Ehlers-Danlos syndrome (particularly type VI, MIM #225400) in the past.21 Corneal ectasia in young children can also be a sequela of inflammation or infection (eg, from cytomegalovirus). It can also be part of Peters anomaly, an anterior segment malfor-mation from a variety of causes (discussed below). Protective goggles are a mainstay of treatment as minimal trauma can lead to perforation and surgical management is challenging.

A B

FIGURE 3 (Conditions with globe enlargement): (A) Familial isolated megalocornea is typically X-linked and symmetrical but is not always. Shown is an affected girl with probable autosomal recessive inheritance who has asymmetric involvement (left cor-nea larger than the right). She was otherwise normal. (B) This girl was initially treated as congenital glaucoma but the large corneal appearance was corneal ectasia secondary to the brittle cornea syndrome. She also had blue sclera and hyperlax joints.

A B

FIGURE 4 (Conditions with Descement tears bands): (A) Haab striae can be seen in the right eye of this young boy who has undergone multiple glaucoma surgeries. The breaks tend to be horizontal and curvilinear. (B) In contrast to Haab striae, Descemet tears from birth trauma tend to be vertical as shown in the affected right eye of a woman who had forceps delivery. In one area a discontinuity in the break results in an atypical scal-loped appearance. She also has high with-the-rule astigmatism and corneal thickening in the affected eye (from reference #28).

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High Myopia

An eye with congenital high myopia (eg, more than -6 diopters of myopia) has both anterior and poste-rior segment enlargement and thus can superficially resemble buphthalmos. However, in buphthalmos corneal changes can be seen (edema, scarring, Haab striae), often with significant oblique corneal astigma-tism that is detectable by retinoscopy. In contrast, high myopia typically does not have corneal findings and has characteristic fundus findings (tessellation, fun-dus, tilted optic nerve head, peripapillary cresent).24 Axial high myopia in an infant should raise suspicion for concurrent retinal dystrophy24 or congenital vitreo-retinopathy25 (in particular Stickler syndrome [MIM #609508, #108300, #604841, #184840]). A-scans can be used as an adjunct to cycloplegic refraction in patient assessment.

Miscellaneous

Large eyes without glaucoma can also be part of over-growth syndromes such as Sotos syndrome (MIM #117550). In addition, a retrobulbar mass that displaces the globe anteriorly, an anatomically shallow orbit, lid retraction, and/or contralateral ptosis can make a nor-mal sized eye appear large.

CONDITIONS WITH DESCEMET TEARS/BANDS

Descemet membrane tears can be a useful confirma-tory sign in borderline pediatric glaucoma cases and are referred to as Haab striae. As uncontrolled IOP enlarges corneal diameter, the relatively inelastic Descemet membrane can tear. Acutely such tears may be associated with focal stromal edema and later with astigmatism, especially if scarring develops. Classically Haab striae are horizontal breaks but in fact can extend in any direction. They may be sinu-ous, crescentic, and even circular. The edges have a tendency to curl inward and can be associated with secondary proliferation of Descemet membrane. Before labeling Descemet membrane changes as Haab striae, one must consider non-glaucomatous causes of Descemet tears/bands.

Birth Injury

Corneal injury during birth is a well-recognized phenomenon that is typically related to the use of obstetric forcepts.27,28 Forceps injury usually occurs

as a result of compression of the globe between the roof of the orbit and the blade of the obstetric forceps, may be initially overlooked because of lid edema, and is unilateral. The resultant corneal edema is often transient but can be associated with scarring. Tears in Descemet generally appear as vertically or oblique striae that are parallel with straight edges and are associated with astigmatism. Later-life onset of corneal decompensation has been described in some cases.27–29

Posterior Polymorphous Corneal Dystrophy (PPCD)

Posterior Polymorphous Corneal Dystrophy (PPCD; MIM #122000, #609140, #609141) is a disorder of metaplasia and overgrowth of endothelial cells characterized by vesicles and bands at the level of Descemet membrane. The PPCD phenotype has been associated with heterozygous mutation in VSX1 (MIM *605020), COL8A2 (MIM *120252), and ZEB1 (MIM *189909) although rare aggressive reces-sive forms also exist. Overgrowth onto the iris can sometimes cause pupillary and iris surface changes as well; when this occurs there is a risk for acquired secondary glaucoma. Most cases are mild and asymptomatic during childhood and thus unlikely to be confused with pediatric glaucoma. The PPCD Descemet bands are classically vertical but can be any direction. The band-like Descemet structures of PPCD also differ from Haab striae in histopathol-ogy and clinical appearance. PPCD bands consist of localized excessive formation of aberrant Descemet membrane, giving both edges of the band an irregu-lar and scalloped clinical appearance.29 Haab striae represent reformed Descemet membrane at the site of a tear and have a smoother outline with one or both edges appearing straight, undulating, or thickened (because of the tendency for torn edges of Descemet membrane to curl). Another distinguishing aspect is that PPCD bands are associated with the nodular vesicles of PPCD. Examination of the parents for signs can be useful when PPCD is suspected; retroil-lumination can show subtle signs.

Miscellaneous

Other potential similar non-glaucomatous lesions at the level of Descemet membrane can occur from cor-neal ectasia (as in Brittle Cornea Syndrome) hypotony (Descemet folds), overt/covert blunt trauma, and endothelial infection (eg, rubella, syphilis).

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CONDITIONS WITH CORNEAL HAZE/SCARRING

Epithelial edema with corneal haze often occurs in severe congenital/infantile glaucoma, with or without associated central corneal scarring. However, in several corneal disorders corneal edema and/or scarring can not only resemble the corneal changes of early child-hood glaucoma but also can result in falsely elevated IOP measures because of associated corneal thickness/stiffness. A lack of buphthalmos in such situations can be helpful in distinguishing these conditions, as increased IOP that causes early onset corneal edema and scarring is also expected to cause some degree of buphthalmos.17

Congenital Hereditary Endothelial Dystrophy (CHED)

Measured IOP can be falsely elevated in some (but not all) children with edematous corneas and increased central corneal thickness as a result of recessive con-genital hereditary endothelial dystrophy (CHED; MIM #217700).17 When measured IOP is high in severe con-genital cases, the differentiation from newborn glaucoma can be challenging. Lack of buphthalmos in a newborn with corneal haze and high measured IOP should raise suspicion for corneal disease rather than glaucoma.17 Careful slit-lamp examination of the cornea in recessive CHED reveals a markedly thick cornea (often approach-ing 1 mm by pachymetry) and a mosaic pattern to the cornea.17 This is unlike the typical pattern of corneal haze in congenital glaucoma, in which the corneal haze tends to be consistently diffuse throughout the cornea with variable secondary central corneal scarring and Haab striae. Corneal thickness in primary congenital glaucoma does not approach that of CHED unless there is obvious secondary corneal scarring (whitening). In fact, central corneal thickness in early childhood glaucoma (without acute edema) is often thinner than average.15 Analysis of SL4CA11 (MIM *610206) can be helpful in confirming the diagnosis of CHED; however, the diagnosis remains clinical as a negative result does not rule out the condi-tion.17 A family history of congenital glaucoma can be misleading in such cases as other family members may have been misdiagnosed.17 Although it is theoretically possible for congenital glaucoma and CHED to coexist in the same patient, more likely than unfortunate coin-cidence of the two diseases would be CHED simulating congenital glaucoma.17

Posterior Polymorphous Dystrophy of the Cornea (PPCD)

As mentioned above, during childhood most cases of PPCD are relatively mild, do not cause significant symptoms, and thus do not cause diagnostic confusion with congenital/infantile glaucoma. Rare severe cases, however, are associated with early childhood corneal edema and photophobia and thus can be mistaken for infantile glaucoma. Such cases may be due to recessive disease rather than the more typical dominant form. Careful examination under sedation and awareness of the condition allow proper diagnosis. As discussed above, in PPCD characteristic aggregates of nodular vesicles and band-like lesions can be appreciated at the level of Descemet membrane. A definitive diagnosis of PPCD, however, does not rule out the possibility of glaucoma. Adhesions can develop between the posterior surface of the peripheral cornea and the iris

A B

C D

FIGURE 5 (Conditions with Corneal haze/scarring): (A) In this infant with primary congenital glaucoma, corneal edema and scarring is accompanied by buphthalmos. Involvement is asym-metric, which is not uncommon. Note the pattern of central scar-ring and thickening in the left eye. (B) This 7-year-old girl was had been treated for glaucoma for years until the diagnosis of congenital hereditary endothelial dystrophy (CHED) was made and confirmed by genetic testing. Although intraocular pressure consistently measured in the upper twenties since birth, there was neither buphthalmos nor optic nerve cupping. Her cyclople-gic refraction was moderate hyperopia. Corneas were thick and had the characteristic mosaic haze of CHED. The right eye is shown. (C) This 6-year-old girl has had worsening photophobia and tearing since she was a toddler. Intraocular pressure could not be taken accurately but there was no buphthalmos, no optic nerve cupping, and a hyperopic refraction. Corneas were thick with stromal haze and multiple vesicles at the level of Descemet membrane, consistent with posterior polymorphous corneal dystrophy (PPCD). On this slit-lamp photograph of the right eye some vesicles are black and others are clear. Children with severe PPCD such as this one are at risk for developing glau-coma. (D) Sclerocornea is a descriptive term and is a phenotype of corneal opacity/scleralization often with peripheral vascu-larization that can be from a variety of genetic or intrauterine causes. Glaucoma can develop and is difficult to assess. This 2-year-old girl was born with opaque corneas with peripheral vascularization and without any evidence for buphthalmos or grossly increased intraocular pressure. Birth history was other-wise unremarkable.

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leading to glaucoma, later in life for mild cases but potentially during childhood in severe cases.29,30

Congenital Stromal Dystrophy of the Cornea

Only a few reports of a congenital hereditary stromal corneal dystrophy (MIM #610048) have been published. The phenotype is caused by heterozygous mutation in decorin (MIM *125255). As has been discussed, cor-neal haze with a lack of buphthalmos in a newborn should raise suspicion for corneal disease rather than glaucoma.

Posterior Amorphous Corneal Dystrophy

To date 12 families have been reported31 with this corneal disorder. In addition to corneal features (partial or com-plete posterior lamellar corneal opacification, decreased corneal thickness, and flat corneas), iris abnormalities (iridocorneal adhesions, correctopia, and iris atrophy) have been described. A lack of corneal edema and buphthalmos and the presence of corneal opacification confined to the posterior cornea are features that dif-ferentiate it from congenital/infantile glaucoma.

Mucopolysaccharidoses and Other Storage Diseases

The mucopolysaccharidoses are a heterogeneous group of disorders in which reduction of lysosomal enzymes leads to accumulation of intra- and extracel-lular glycosaminoglycans. Corneal haze in these cases can be from such deposition alone, although true glau-coma can develop as well. Corneal haze from deposi-tion alone is typically bilateral and of later infantile rather than congenital onset. Classic dysmorphic features can be helpful in identifying a young child with mucopolysaccharidosis. It is beyond the scope of this article to go through the various classifications and subtypes for this challenging group of disorders.26 Other similarly challenging metabolic diseases that can cause corneal haze include the mucolipodoses and sphingolipidoses. In addition, cystinosis (MIM #219800) can result in corneal haze during early child-hood, but careful slit-lamp examination reveals the characteristic crystalline deposits.

Peters Anomaly

Peters anomaly refers to a spectrum of phenotypes from different causes that include central absence

of corneal endothelium, Descemet membrane, and posterior corneal stroma with variable degrees of corneal-lenticular and irido-lenticular adhesion.5 The phenotype varies from subtle posterior corneal inden-tation to dense corneal opacity that precludes visual-ization of the anterior segment; although the lesion is typically central it can be paracentral as well. Peters anomaly is genetically heterogeneous; for example, cases have been associated with underlying heterozy-gous PAX6 mutation and with underlying recessive CYP1B1 mutations.5 The possibility of infectious (eg, herpetic) or iatrogenic cause (eg, from amniocentesis) should also always be considered. While the corneal changes can cause confusion with glaucoma when in fact there is none, there is a risk for concurrent glau-coma in Peters anomaly, particularly when it is due to CYP1B1 mutations. Ultrasound biomicroscopy is invaluable for proper assessment of both the ante-rior and posterior segments in babies with opaque corneas.

Sclerocornea

Sclerocornea is a phenotype of corneal opacity/scleralization often with peripheral vascularization that can be from a variety of genetic or intrauter-ine causes.32 Coexistent glaucoma is possible but glaucoma assessment is challenging because IOP, refraction, and disc appearance cannot be assessed well. Corneal surgery can be considered in one eye; however, in many cases only comfort measures are recommended. Again, ultrasound biomicroscopy is invaluable for assessment of children with opaque corneas.

CONDITIONS WITH IRIS ATOPHY/MALFORMATION

In primary congenital/infantile glaucoma, iris atro-phy is often secondary to increased IOP. In devel-opmental glaucoma, iris stromal changes can be a developmental malformation in conditions such as the Axenfeld-Rieger spectrum and aniridia. Rarely, severe endothelial metaplasia in PPCD can cause early onset iris changes and a risk for secondary glaucoma. Therefore, the presence of iris abnormalities should raise suspicion for glaucoma and it is not surprising when early childhood glaucoma is diagnosed in a child with congenital iris malformation. Two rare situations exist, however, in which iris abnormality and corneal haze coexist without documented risk for early child-hood glaucoma. One is recessive cornea plana (MIM #217300) and the other is posterior amorphous corneal

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dystrophy as discussed above.31 Unlike other pheno-types of congenital iris malformation, for these two conditions there is no apparent increased risk for early childhood glaucoma and thus for them the diagnosis of early childhood glaucoma should be made with caution.

CONDITIONS WITH OPTIC NERVE CUPPING

As in adults, in young children high IOP leads to optic nerve cupping. Vertical elongation is a useful confirma-tory sign for pediatric glaucoma although central sym-metric cupping can occur as well. Focal notching of the cup as is typically seen in affected adults is not com-mon in young children; inferonasal notching in a child should raise suspicion for a colobomatous defect. Also unlike in adults, in young children glaucomatous cup-ping can be reversible after successful IOP control. Optic neuropathies are usually distinguishable from pediatric glaucomatous discs by the accompanying neuroretinal rim pallor. Common non-glaucomatous congenital causes of optic nerve cupping such as coloboma, morn-ing glory abnormality, and optic nerve pit are usually recognizable by their distinct features. However, there are certain forms of congenital optic nerve cupping that are more likely to be confused with glaucomatous cup-ping in children (as well as in adults).

Physiological Cupping

When evaluating the optic nerve cupping, one needs to take into account the size of the optic disc. Eyes with larger optic nerve heads have larger optic nerve cups

than eyes with smaller optic nerve heads and thus may appear to have loss of disc substance when in fact the amount of tissue in the neuroretinal rim is normal. An extreme example of this phenomenon occurs with megalopapilla, an enlarged optic disc (greater than 2.1 mm diameter) with no other morphological abnor-malities.33 Although the cupping is typically central, the increased cup-to-disc ratio in this condition may be mistaken as glaucomatous.33 Examination of parents can be helpful to confirm suspected physiologic cup-ping as it is often familial.

Papillorenal Syndrome

The papillorenal syndrome (MIM #120330) is a disor-der of angiogeneisis with a wide phenotypic spectrum that predominantly involves the central optic nerve head vasculature and the kidney. Although heterozy-gous mutation in PAX2 (MIM*167409) underlies some

FIGURE 6 (Congenital iris atrophy malformation): Recessive cornea plana is a distinct ocular phenotype characterized by small flat corneas and specific for recessive KERA mutation. Corneal haze and iris hypoplasia can occur as shown in the right eye of this young boy, but there is no documented increased risk for early childhood glaucoma.

A B

C D

FIGURE 7 (Conditions with optic nerve head cupping): (A) This 5-year-old boy referred for suspicious cupping in his right eye had a coloboma of the optic disc. Note the inferonasal cupping. Anterior segments were normal and refraction was hyperopic. In his contralateral eye there was a large inferonasal chorioreti-nal coloboma (not shown). (B) This 5-year-old boy had normal intraocular pressure, a hyperopic refraction, and large optic nerve heads with associated large cupping (megalopapilla). There was neither buphthalmos nor corneal abnormality. The left eye is shown. Note the relatively short distance between the disc center and the fovea. (C) The right “vacant disc” of an infant with papillorenal syndrome is shown. Multiple cilioretinal arteries exit the disc, the retina is hypoplastic, and there is no retinal artery circulation (from reference # 35). (D) This 6-month-old girl with a history of prematurity and developmental delay was referred for glaucoma treatment. In fact she had a bilateral static optic nerve hypoplasia associated with periventricular leu-komalacia. The right eye is shown (which, in addition to vertical cupping, has an inferotemporal wedge defect of the nerve fiber layer and is excylotorted). After years of follow-up she has no evidence of glaucoma.

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cases, the diagnosis remains clinical with optic nerve head findings being the most consistent feature.34 There is variable central optic nerve head excavation (“vacant discs”) which can be confused with glau-comatous cupping but does have distinctive features. Central vessels emanating from the disc are absent. Instead, cilioretinal vessels originate at the periphery of the disc where they circumferentially make hairpin turns over the neuroretinal rim toward the retina. The absence of central retinal vasculature can be associ-ated with retinal hypoplasia. Structural and functional renal changes may or may not cause significant renal insufficiency in childhood or adulthood. The papil-lorenal syndrome is likely under-recognized, particu-larly in patients treated for low-tension glaucoma who have a history of idiopathic renal failure. Recognition of the specific congenital optic nerve findings can allow prompt diagnosis prior to the onset of renal dysfunction35 and avoid unnecessary anti-glaucoma treatment.

Optic Nerve Hypoplasia in Periventricular Leukomalacia

Periventricular leukomalacia is the result of interu-terine hypoxic-ischemic injury to the white matter of the developing brain that is more common in prema-ture infants and is associated with visual cognitive impairment, inferior field constriction, and spastic diplegia.36 In addition, periventricular leukomalacia can be associated with a unique form of optic nerve head hypoplasia in which the disc size remains nor-mal but cupping is increased.36, 37 This is thought to be from retrograde transsynaptic degeneration of retino-geniculate axons after the scleral canals had already established normal diameters. This optic nerve head appearance can be mistaken as glaucomatous when a premature child is screened for retinopathy of prema-turity unless the treating ophthalmologist is aware of this phenomenon,36 which should be suspected in any child with optic nerve cupping and a history perinatal brain hypoxia.

SUMMARY

Usually the diagnosis of early childhood glaucoma is straightforward. However, ophthalmologists who care for children with glaucoma must always keep in mind conditions that can be mistaken for pediatric glaucoma. In my experience confusion most often occurs in infants with isolated megalocornea, recessive CHED, and/or optic nerve hypoplasia that is related to perinatal brain hypoxia and manifests as optic disc cupping.

Declaration of interest: The author reports no conflict of interest. The author alone is responsible for the con-tent and writing of the paper.

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