Amaya2003.pdf

SURVEY OF OPHTHALMOLOGY VOLUME 48 • NUMBER 2 • MARCH–APRIL 2003

MAJOR REVIEW

The Morphology and Natural History of Childhood Cataracts Luis Amaya, MD, David Taylor, FRCOph, Isabelle Russell-Eggitt, FRCOph, Ken K. Nischal, FRCOph, Dora Lengyel, MD Department of Ophthalmology, Great Ormond Street Hospital for Children, London, United Kingdom Abstract. The morphology of congenital cataract reflects a combination of the timing and nature of the cause, the anatomy of the lens including its capsule, its development, and changes that take place with time. Morphology may variably affect prognosis, give a clue to the etiology and the age of onset and, in an isolated case, sometimes suggest heritability. The spectrum of morphological variations is enormous and can be complex. A comprehensive approach is to classify the variations according to the area of the lens involved, and sub-dividing them by a detailed description of the shape and appearance. Each specific morphological type is then analyzed determining the etiology, visual prognosis, and management. The use of gene markers has allowed many of these variations to be identified and categorized. Cataracts in childhood can involve the whole lens, in which case they are called total, Morgagnian, or disk-like. They can affect only the center of the lens: lamellar, nuclear, oil droplet, cortical, or coronary. They can be anterior: anterior polar, anterior subcapsular, or anterior lenticonus. The posterior aspect of the lens can also be affected in different fashions: Mittendorf’s dot, posterior lenticonus, posterior cortical cataracts, or posterior subcapsular. There are five more forms that must be described separately: punctuate lens opacities, sutural cataracts, coralliform or crystalline, wedge-shaped, and persistent hyperplastic primary vitreous. (Surv Ophthalmol 48:125–144, 2003) © 2003 by Elsevier Science Inc. All rights reserved.) Key words. cataract • childhood • embryology • infancy • morphology • natural history

I. Introduction

tions. The use of gene markers is helping to identify some forms and variations associated with a specific locus in hereditary cases. The visual prognosis may also vary according to the morphological type. A description of the morphological features of lens opacities may help to initiate management lines, diagnostic work-up, therapeutic approach, feasibility of intraocular lens implantation, and visual prognosis. Even in adults, there is little consensus as to the visual significance of certain lens opacities between surgeons and researchers.73 This article describes, reviews, and discusses the morphology of different lenticular abnormalities in children.

Lens opacities in infancy can have a wide spectrum of presentations and variations, ranging from a minute white dot in the anterior capsule to dense, total opacities involving different structures of the lens. The nucleus can be the only structure affected in some patients, whereas in others it is clear and spared, but the cortex is involved displaying different patterns of opacities; in some other patients, the capsule is abnormal, leading to alteration and opacification of cortical lamellae. For many years, these striking morphological variations have puzzled clinicians and researchers, who have tried to explain their cause.49,142 Even now, we tend to ignore the reasons for the various presenta125 © 2003 by Elsevier Science Inc. All rights reserved.

0039-6257/03/$–see front matter doi:10.1016/S0039-6257(02)00462-9

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II. Lens Embryology and Growth The morphology of a cataract is largely determined by the anatomy of the lens and the timing and nature of the insult that caused the abnormality by altering the embryogenesis. The lens placode appears on the optic vesicle which protrudes from the forebrain,118 around the 25th day of gestation, it is a thickening of the surface ectoderm, a single layer of cuboidal cells, that invaginate into the neural ectoderm of the optic vesicle as the lens pit, becoming free from the surface by the 33rd day. The posterior cells elongate as primary lens fibers that obliterate the lumen of the lens vesicle:133 the retina largely determines this cytodifferentiation. The tiny developing lens is surrounded by a basement membrane that will become the lens capsule and is filled with nearly structureless primary lens fibers, cells that expel their nuclei, mitochondria, Golgi bodies, and endoplasmic reticulum. This structure becomes a spherical optically clear embryonic nucleus of 0.35 mm in diameter,133 which stays unchanged throughout life,118 and is seen inside the Y sutures in the fully developed eye. Equatorial, secondary lens fibers, derived from the anterior epithelium, migrate anteriorly under the anterior epithelium and posteriorly directly beneath the capsule118 to meet each other at the sutures which can be seen easily with slit-lamp microscopy as an upright anterior Y, and an upside down posterior Y; the limbs of the Ys are often branched. Fibroblast growth factor (FGF)137 may induce this differentiation. After birth, the equatorial fibers grow to form the cortex, meeting at more complex and less well-marked sutures: this growth continues until very shortly after death. The tertiary vitreous condenses within the space between the ciliary body and the lens equator forming the suspensory ligament of the lens at the fifth month of gestation.118 The developing lens requires nutrition that is obtained through the tunica vasculosa lentis (TVL), which is a vascular network, supplied posteriorly by the hyaloid artery, a branch of the primary dorsal ophthalmic artery, and anteriorly from an anastomosis with vessels in the pupillary membrane.118 The TVL is first seen at about 35 days, and is most prominent at 65 days; it gradually regresses at about 85 days; by term birth, only whispy remnants of the pupillary membrane are left, and a vestigial hyaloid artery (known as a Mittendorf’s dot) is attached to the axial posterior surface of the lens.

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nant pattern. As in many autosomal dominant conditions, phenotypic heterogeneity is common in many of these.7,36,99,126,185 Within a pedigree various morphologies can occur. It is not as simple as one gene mutation causing one phenotype: other genes may modify expression. There are interocular185 and intrafamilial morphological differences within a pedigree, especially when inherited as an isolated abnormality. This was noted in a study99 in which eight hereditary phenotypes were identified. An interesting study of a four-generation family with members affected with isolated polymorphic autosomal dominant congenital cataract demonstrates clear evidence of allelic heterogeneity.68 Cerulean and zonular pulverulent cataracts display this same kind of heterogeneity although the abnormality lies in the same locus at chromosome 13.126,221 Likewise, variations between dense nuclear opacities and pulverulent type within the same family, and even the two eyes of same individuals, have been described.185 In contrast, as is the case with anterior polar cataracts, the same morphology can be the consequence of alterations in different loci of different chromosomes.99,144,178 Certain phenotypes (lamellar, pulverulent, polymorphic, coralliform, and cortical) seem to have good visual prognosis.70 PAX6 mutations can occasionally cause anterior polar cataracts without aniridia.55 A. CATARACTS INVOLVING THE WHOLE LENS

Cataracts involving the whole lens are often of early onset and, if so, have a profound effect on visual prognosis: they may demand early surgery.39 1. Total Cataracts A total cataract represents a general opacity of all the lens fibers:54 some lenses are completely opaque when first diagnosed. In other cases, they develop from lamellar or nuclear cataracts. They are frequently bilateral118 and may progress.22 Cataracts involving the whole lens occur in Down syndrome, in acute metabolic cataracts, in congenital rubella (where shaggy nuclear cataracts are more common), and can also be seen in familial46 or sporadic cases105 as well as in some rare syndromes.31,43 Surgery is usually indicated, and aggressive surgical management is mandatory if a good visual prognosis is to be achieved. They are also cosmetically significant, so in cases where a good visual result is not expected, surgery may be indicated for this reason. Total cataracts have also been associated with posterior lenticonus. 2. Congenital Morgagnian Cataracts

III. Heterogeneity, Specific Morphological Types, and the Effect of Morphology on Visual Prognosis Many cataracts are genetically determined, the majority of them being inherited in an autosomal domi-

These are uncommon, total, dense cataracts, named after Giovanni Morgagni who described them in 1762; the outer zones of the lens become liquefied, while the nucleus remains intact. This allows the nucleus to fall by gravity in any direction, depending on the position

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Fig. 1. Morgagnian cataract: intact nucleus in liquified outer zones falls by gravity in any direction. Left: sitting position, Middle: upside down, Right: lying on the right side.

of the head (Fig. 1).20 The milky fluid was thought to cause glaucoma after surgery in days before aspiration.37 Eventually the fluid may be reabsorbed so that the anterior and posterior capsules adhere above the displaced nucleus;20,54 sometimes they can even completely reabsorb.14,20 3. Disk-like and Membranous Cataracts Disk-like and membranous cataracts represent varying stages of reabsorption of the lens, which leaves either a disk of lens material or a bag of milky or crystalline substance that can be dense and completely opaque or thin and transparent; alternatively, the anterior and posterior capsules fuse together (membranous cataract).54 Reabsorption, which has been recognized for centuries,1,181 can occur after trauma or can present spontaneously. It has been described in congenital rubella,16,57,192 in the Hallermann-Streiff syndrome,63,117,194, 206,225 it is common in PHPV,222 and has been described in aniridia,228 in Lowe’s syndrome,77,117,211 and in a patient with the Pierre-Robin sequence;176 it may also occur after rupture of an anterior lenticonus.204 When reabsorption occurs mainly centrally, the lens may take on a hollow doughnut,22 Polo, or lifebuoy sweet shape.38,74 Failure of development or reabsorption may give rise to a sector-shaped membranous cataract, where a dense opaque membrane of whitish-grey tissue replaces the cortex.4 Surgery may be required; these cases are technically more difficult, and intraocular lenses are unlikely to be inserted easily into the bag. Ultrasound biomicroscopy may be helpful in defining the surgical approach. Sometimes the membrane is very thick.208

nucleus and cortex22,117 (Fig. 2). It represents several generations of secondary lens fibers, which have become opacified in response to an insult when these fibers were at their most metabolically active.22 The opacity may be so dense as to render the entire central region of the lens completely opaque, or so translucent that vision is hardly if at all impeded.54 They are often inherited as an autosomal dominant trait.126 Typically, they are bilateral but slightly asymmetrical, sometimes with different degrees of opacification in different meridians117 (Fig. 3); they are composed of minute white dots in one or more layers of the lens, not involving the embryonic nucleus, though sometimes involving the fetal nucleus. They are usually sharply separated94 from a clear cortex outside them. They are often incomplete,105 and they may have projections from their outer edges known as riders or spokes (Fig. 3). There may be a tendency to increase in density over a long period;40 some may become smaller with increasing patient age by a process of compaction.25 This reduction in equatorial diameter may result in improvement of vision in affected children. However, three families have been observed in which the cataract increases in size by the addition of new

B. CENTRAL CATARACTS 1. Lamellar or Zonular Cataracts

Lamellar or zonular cataracts are common94,105 forms that involve one or more layers or zones of the lens, as a shell of opacity,101 sandwiched between clear

Fig. 2. Lamellar cataract with small riders.

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Fig. 3. Left: Lamellar cataracts, right with riders in retro-illumination. Right: Partial lamellar lens opacities in retroillumination.

opaque lamellae superficial to the congenitally formed opaque lamella.25 The visual prognosis, especially in partial cataract, is probably better than in many other morphological types;40,156,157 many cases can be managed conservatively41,71 and surgery in infancy is rarely necessary. There is often a marked interocular185 and intrafamilial variability.5 Zonular cataracts have been mapped on chromosome 1q.171 The linkage of a gene causing a unique form of autosomal dominant zonular cataracts with Y-sutural opacities to chromosome 17q11-12 in a fourgeneration family has been reported.155 The zonular pulverulent (CZP1) has been mapped to chromosome 1q190 and 13q (CZP3).126 The CZP3 form of cataract is thought to be due to mutations in the gene encoding connexin-46 (CX46). More recently an autosomal recessive late onset progressive pulverulent cataract with a disease locus at 9q13-q22 has been identified.91 The CZP1 form of cataract may be caused by mutation in the alpha-8 subunit of the gap junction protein.227 Table 1 lists the gene loci linked with cataract type, and Table 2 summarizes the morphology and etiology of the cataracts discussed in this review. In general, lamellar cataracts have a better prognosis than other morphological types.41 They can develop gradually through childhood with a translucent opacity that is not too dense, thus allowing a fairly adequate visual development without affecting the vision. Some infants may not need surgery.41,71 However, some have a worse visual outcome than others if the opacity starts earlier during the lens development, if they are more dense, and if they involve the center of the lens; in such cases, profound ambyopia is common. Surgical management, when indicated, is easy, usually there is no microphthalmos associated, and in the bag implantation of intraocular lenses can be an option at any age. 2. Central Pulverulent Cataracts Central pulverulent cataracts are composed of myriad (pulverized) tiny dots (Fig. 4). They are nonprogres-

sive, usually occurring bilaterally and vision is rarely affected.22,54 They may be familial as in the autosomal dominant Whalsay cataract,170 which affected descendants of a Dane, born in 1745, who immigrated to the Shetland Isles. A form of central pulverulent cataract was an early example of genetic linkage to chromosome 16.134 This central pulverulent type described as a “sharply defined circular disk placed deep in the lens between the nucleus and the posterior pole” by Nettleship and Ogilvie in members of the Coppock family,150 was considered a specific type of lamellar cataract which the authors distinguished from lamellar cataract since it involves the embryonic nucleus but this was without the benefit of the slit-lamp microscope. Rosen177 found by slit-lamp examination that this type of cataract was not discoid but central pulverulent and that this morphological form was not confined to the Coppock family; he suggested that the name Coppock was deleted in favor of the term cataracta pulverulenta centralis. The eponym seems to have stuck, being used in the publication describing a gene locus123 in 1987. Some authors classify Coppock cataracts with nuclear cataracts99 because the Coppock cataract involves the embryonic nucleus; this, and the pulverulent nature is what distinguishes it from others like the polymorphic cataract described by Rogaev,175 which does not involve the embryonic nucleus but has opacities extending from the fetal nucleus to the cortex. It is caused by mutation in the gamma crystallin.152 The CAE cataract that is linked to the Duffy blood group affects both the embryonic and the fetal nuclei and is 4 mm in diameter.189 A very large pedigree has been described by Priestly Smith.193 Marner134 described the Danish Olson family with 965 persons in nine generations. The ratio of the affected to the nonaffected was 70:76. The typical cataract appears as fine, dispersed, pulverulent opacities in the embryonic nucleus; they are reported as being progressive, showing later zonular or posterior subcapsular opacities, sometimes along the Y sutures.

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Gene Loci Linked With Cataract Type Cataract Type Total Volkman, nuclear Posterior Polar Posterior Polar Posterior Polar Zonular pulverulent Zonular pulverulent Pulverulent Coppock-like Breadcrumb-like Polymorphic Polymorphic (pulverulent) Nuclear and lamellar Nuclear Anterior polar Zonular, sutural Zonular Central nuclear Central pouchlike sutural Cerulean Cerulean Punctate Nance-Horan syndr Nance-Horan syndr

Pattern inheritance

Author and reference 189

AD PD AD AD AD AD AD AR AD AD AD AD AD X-Linked AD AD AD AD AD AD AD X-LR X-LR

Semina et al Eiberg et al58 Yamada et al227 Ionides et al100 Berry V et al11 Renwick and Lawler171 Bateman et al6 Heon et al91 Lubsen et al123 Chang-Godnich A et al32 Rogaev et al175 McKay et al126 Marner et al134 Francis et al69 Berry et al12 Padma et al155 Ouax-Jeunken et al163 Vanita et al214 Armitage et al2 Kramer et al113 Stephan et al202 Lewis et al120 Zhu et al229

Gene locus 10q24-25***** 1p36 20p12-q12 1p 11q22-q22.3*** 1q21-25 17q23.1-23.2** 9q13-q22 2q33-36* 19 2q33-35 13q11 (CX46) 16q22.1 Xp22 17p 17q11-12** 21q22-3*** 15q21-22 17q24 22q11.2** 2q33-35* Xp22.2-22.3 Xp22.2-22.3

AD  autosomal dominant, AR  autosomal recessive, X-LR  x-linked recessive *gamma crystallin, **beta A1 crystallin, ***alpha crystallin, ****CX46 Connexin 46, *****PITX3

They may progress in density and size. The gene locus has been linked to chromosome 16. Stabile198 described a large kindred in Italy with 64 members in four generations, 25 of who were affected by a form of congenital puverulent cataract with diffuse fine opacities in both the nucleus and the cortex. The involvement of the cortex distinguishes this form from the zonular pulverulent cataract of Nettleship and Ogilvie.

They presumably are related to a transient disturbance of lens metabolism; although in most of them no underlying cause is usually found. However, they may occur in cases of known transient metabolic disturbance, such as galactosemia,78,182 hypoglycemia,140 or hypocalcemia.22 The underlying pathogenic mechanism may be related to a breakdown of the lens fiber membrane.46 In some cases several layers of opacity are interposed between normal lens fi-

TABLE 2

Morphology and Etiology of Cataracts Total Disk like Anterior polar Anterior subcapsular Anterior lenticonus Posterior cortical Posterior subcapsular Lamellar (zonular) Nuclear Central pulverulent Cortical Cerulean Coraliform Wedge-shaped Punctate

Down,10,44.metabolic, rubella16,57 AD,46 sporadic,105 syndromes31 Trauma, rubella,192 Hallermann-Streiff,63,117 PHPV,222 aniridia,228 Lowe,17,117 ruptured anterior, lenticonus204 AD,99,139 aniridia, retinoblasoma,21 Piere-Robin Uveitis, trauma, irradiation, atopic, skin, Alport198 Sporadic,42 X-Linked,76,116,216 AD,15,28,76,95,160,216 AR,160 hyperglycinuria,165 microcornea,15 Duane syndrome29 AD129 Myotonic dystrophies,60 Turner’s,60 Fabry’s,112 NFM 216 AD,134,150 galactosemia,78,182 hypoglicemia,140 hypoglycemia22 AD,180 rubella,22,57 oil droplet,8,26 X-Linked,69 galactosemia8 AD,162,170 AD99 AD22 AD88,149 Conradi,87 Stickler,75,187 NF2, Fabry67 Down,10,44 Lowe carriers,61 Nance-Horan carrier,13 Fabry67

AD  autosomal dominant, AR  autosomal recessive

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Fig. 4. Top left: Central pulverulent cataract with myriads of tiny dots. Top right: Central Pulverulent (Coppock) cataract. Bottom: Central pulverulent (Coppock) cataract in retro-illumination.

bers, indicating periodic activity of the pathogenic factor.140 In other cases all the layers were involved and the cataract was maturing or even a bilateral dense lamellar cataract was found in two patients with a malformation of pilo-sebaceous follicles.146 Basti5 described 24 out of 48 members in a family with morphological identical zonular cataracts in the second generation. In the third generation, the members showed morphologic heterogeneity with the zonular opacity varying from a uniform lamella to a segregation of dots. Six patients had a uniform zonular component, a pulverulent fetal nucleus comprising discrete white dots and well defined, erect Y-shaped anterior and inverted Y-shaped posterior sutural cataracts within the area enclosed by the zonular component. There were no radially oriented opacities seen in any of the lenses. Two additional members had cataracts with zonular components consisting of fine dots. The pulverulent fetal nucleus and sutural opacities seen in the six former patients were also present but less well defined. Lamellar cataracts may be combined with anterior and posterior polar or nuclear opacities.105,230

(Fig. 5). These calcified white dots may escape lens aspiration and can be found in the anterior chamber of the aphakic eye. 4. Nuclear Cataracts These are opacities of more or less the entire embryonic or fetal nucleus,99 similar to lamellar cataract, and are often not highly visually significant. The density varies greatly from fine dots to a dense, white and chalk-like, central cataract. They are static and as the lens grows, the central opacity becomes relatively less significant. The condition is usually bi-

3. “Ant Egg” Cataracts Sometimes a central cataract is composed of larger grainy white dots that are caused by secondary calcification:184 these are known as “ant egg” cataracts173

Fig. 5. “Ant egg” cataract caused by secondary calcification.

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lateral.22, 54 They are often combined with opacified cortical fibers encircling the nuclear opacity, which are referred to as riders.117 They may be combined with opacities of the sutures.99 Vogt’s anterior axial embryonic cataract is a visually insignificant group of opacities lying near, but posterior to the anterior upright Y. Vogt219 thought that it might be remnants of primary lens fibers; Mann133 felt they were more closely related to sutural development. Crystalline nuclear cataracts have been described in association with an abnormality of the hair.47 Bilateral nuclear opacities are the most common autosomal dominant inherited form of cataract.180 Many large dominantly inherited pedigrees have been reported, various with a high degree of penetrance but with some variability in expression.50,97,124,180,185 Francis et al have recently identified a locus for isolated cataract on chromosome Xp22.69 Dense nuclear opacities surrounded by a relatively clear cortex have been described in the congenital rubella syndrome.22,57 A combination with posterior polar opacities was the most frequent combination found in a large study of 146 eyes examined in northern India.105 Nuclear autosomal dominant opacities may be associated with microphthalmos, and have a higher risk of developing aphakic glaucoma after cataract surgery.157 In certain patients, conservative management is preferred if moderate vision is present to avoid postoperative complications. However, if vision is severely impaired, surgery is necessary. 5. Oil Drop Cataracts This is classically seen in infants with galactosemia. There is a central area of different refraction to the surrounding lens that looks like an oil droplet floating on water. Provided the metabolic condition is swiftly resolved, there is no residual trace, but if late treated or if the diet is not strictly adhered to, a lamellar opacity may develop and increase. Other forms of cataract occur in galactosemia, including posterior subcapsular,

or small nuclear and cortical opacifications.8 They may regress if dietary control is instituted early.8,26 A similar ophthalmoscopic appearance (but not, of course, cause) occurs in posterior lenticonus.188 6. Cortical Cataracts Cortical cataract is unusual in childhood, a few families have been described with an autosomal dominant inheritance.99 The onset of the cataract may be post-natal, at least the visual defect may occur after infancy. The nucleus is not involved; the opacity is restricted to the outer cortex. 7. Cerulean, Floriform, or Coronary Cataracts These frequently seen opacities have in common a sky-blue or sea-green (cerulean) hue (Fig. 6), and can be quite beautiful on slit lamp microscopy;218 other colors may be seen, including red, such as in hyperferritinemia, or brown and opalescent white, resembling breadcrumbs.32 They are autosomal dominant, early onset, bilateral, largely stationary, and visually insignificant cataract, situated in the peripheral cortex.22 They are often concentrated in the equatorial region of the lens, and they have a variably sized dot-like shape, sometimes they are elongated. The cerulean cataract phenotype has been genetically mapped at chromosomal region 17q242 and 22q11.2-q13.1.114 Coronary cataracts are common elongated, or clubshaped cerulean opacities that are concentrated in a crown-like ring around the equator of the lens. There is usually no significant effect on vision.22 The pathogenesis and embryological origin of these cataracts is obscure. Koby’s floriform cataract111 (Fig. 7) is an autosomal dominant form seen around the sutures, with oval or annular elements, like the petals of a flower.22 C. ANTERIOR CATARACTS

Anterior polar cataracts are frequently hereditary and even if seen in an isolated case may be new muta-

Fig. 6. Left: Cerulean cataract, opacitites with sky-blue or sea-green hue. Right: Same patient as 6a in retro-illumination.

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Fig. 7. Left: Floriform cataract, elements like petals of a flower around the sutures. Right: Floriform cataract in retro-illumination.

tions, with recurrence risks to the patients’ children. Generally, the visual prognosis is good. 1. Anterior Polar Cataracts a. Dot-like Anterior Polar Cataracts This relatively common opacification was described early in the 20th century;37 these are tiny white dots on the anterior surface of the lens in the axial area that probably represent abnormalities of lens vesicle detachment, they can be unilateral or bilateral; when bilateral, they are usually symmetrical, a reminder of the lens being normal.54 They are composed of tiny dots, sometimes formed like a star (cataracta stel-

lata).92 They vary in size22,54 from one case to another, from just a wrinkling of the capsule to up to a few millimeters,102 and although they are often not, in themselves, visually significant,94 they may be associated with refractive errors19 that can cause amblyopia and strabismus.102 They are visible without a microscope, which is why they are often diagnosed soon after birth117 (Fig. 8). Usually static, they may occasionally progress102,147 and become visually significant. Some cases are inherited as an autosomal dominant trait.139 They have been described in association with a familial 3:18,178 and a 2:14 chromosomal translocation.144 A new locus is identified on the

Fig. 8. Top left: Dot-like anterior polar cataract. There are two cataracts, the larger above and the smaller below, outlined in a light reflex. Top right: There are two anterior cataracts: The anterior one (above the purkinje image of the slit lamp mirror) involves the capsule, the posterior one in the anterior cortex. This patient’s son had anterior polar cataracts. Bottom: An anterior polar cataract with stress lines in the anterior capsule.

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Fig. 9. Left: Plaque-like anterior polar cataract with remnants of the pupillary membrane. Right: Small plaque-like anterior polar cataract with remnants of the pupillary membrane in retro-illumination.

short arm of chromosome 17,12 locating the gene to the region 17p12-13.99 They are very frequent in aniridia and have been reported in association with retinoblastoma21,72 and cerebral malformations.158 There are families described with anterior polar cataracts and cornea guttata.52,53,151,210 Most cases do not warrant surgery, if surgery is indicated, the anterior capsulorrhexis is liable to tear out. All cases should be followed throughout their years of visual development. In cases where visual function is equivocal, careful visual assessment, including the use of forced choice preferential looking, is mandatory. Cycloplegic refraction is essential as there may be associated astigmatism associated with radial capsular wrinkle formation from the central opacity.19 Association with corneal astigmatism has also been reported.18 Rarely is there sufficient progression of the opacity to require surgery. b. Plaque-like Anterior Polar Cataracts Occasionally these axial, plaque-like opacities are associated with a persistent pupillary membrane22 (Fig. 9). The embryological origin may be different: perhaps

the dot-like opacities are related to abnormalities of lens placode invagination, and lens vesicle detachment, whereas the plaque-like ones are caused by abnormalities of pupillary membrane regression. Some cases of persistent pupillary membrane may appear to be associated with a plaque-like anterior polar cataract,139 but may be separable at surgery;203 caution is advisable in undertaking such surgery. They may be associated with corneal opacities.22 The management is similar to the dot-like variety: surgery is indicated only if it interferes with the development of vision or if in an older child the vision is inadequate for the child’s educational and social needs. Dilating the pupils may sometimes improve vision. c. Anterior Pyramidal Cataracts These are the severe form of dot-like opacities; these probably also represent anomalies of lens vesicle detachment; they are larger axial opacities than the dot-like anterior polar cataracts, they may even extend anteriorly and, rarely, fuse with the cornea (Fig. 10), which may be opaque at this area.94 They are fibrous, more likely to be visually significant than ante-

Fig. 10. Left: Small anterior pyramidal cataract. Right: Anterior pyramidal cataract extending anteriorly and fusing with cornea in a patient with aniridia.

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rior polar cataracts, and can even progress. They may become detached209 and form an anterior chamber foreign body;23 surprisingly, they cause little reaction over a number of years. There may be an associated anterior subcapsular lens opacity that may progress, in which case surgery is the usual outcome. They are usually bilateral and bilaterally symmetrical. Histological studies demonstrate a reduplication of the lens capsule that effectively surrounds a polar opacity composed of spindle-shaped epithelial cells and collagen fibrous tissue, with a notable absence of epithelial cells at the base of the pyramidal opacity; there is only an extremely thin lens capsule separating the pyramidal cataract from the anterior cortical lens fibers.223 It has been suggested that the progressive cortical opacification involved in certain pyramidal cataracts is due to epithelial cell dysfunction.34 When hereditary, dominant inheritance pattern is the rule.54 2. Anterior Subcapsular Cataracts Anterior subcapsular cataracts are usually associated with acquired disease such as uveitis, trauma, irradiation, or atopic skin disease (where the lens opacity has a classic shield-like appearance), but they may be part of a more widespread cataract; they may rarely be associated with anterior lenticonus, such as that seen in Alport’s syndrome, or with a pulverulent cataract.198 Opacities may be subtle without significantly affecting vision, however, in some patients, vision is reduced, and surgery needs to be considered. The exact role of connective tissue growth factor in the etiology of anterior subcapsular cataracts is unclear despite evidence of its expression in such lens opacities.197,226 3. Anterior Lenticonus Anterior lenticonus (Fig. 11) is less common than the posterior variety, and it is most frequently encoun-

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tered in association with Alport’s syndrome of nephrotic haematuria and deafness. The lenticonus may be a manifestation of a basement membrane disorder;81 it can be congenital and is found in about 10% of affected young children,103 but may increase in frequency with time as larger series including older patients show an incidence of up to 30%.3 Cataracts are not usually associated, except the posterior subcapsular opacities associated with steroid treatment. Anterior lenticonus has also been associated with Lowe’s77 and Waardenburg’s syndromes.204 Even if there are no lens opacities, high astigmatism due to the lenticonus may affect the vision significantly, requiring surgery. D. POSTERIOR CATARACTS

Some posterior cataracts such as Mittendorff’s dots (which never require surgery) and posterior lenticonus may have a good visual prognosis, in the latter because the visual defect may have a late onset. Other posterior cataracts, if of congenital onset, may be associated with a poor visual prognosis. 1. Mittendorf’s Dot Mittendorf’s dot, also called the hyaloid body,205 represents the remains of the anterior end of the hyaloid artery. It appears as a small axial or nasally paraxial grey-white dot opacity at the posterior apex of the lens, often associated with a thread-like structure, which represents remains of the anterior end of the hyaloid artery. It is, in itself, visually insignificant unless it is large which is rare, and may then represent a mild form of persistent hyperplastic primary vitreous (PHPV). Occasionally it is associated with posterior lenticonus.28,110,133 Sometimes, it may be associated with a persistent hyaloid artery, another similarity with PHPV. Usually they are stable, not requiring surgery, but progression has been noted.94 2. Posterior Lenticonus

Fig. 11. Anterior lenticonus. The slit beam on the anterior lens surface is more curved than usual. (Courtesy of Mr. J.J. Kanski.)

Interest in lenticonus (Fig. 12), which was described in the 19th century,60,141,145 increased with the widespread use of the slit-lamp microscope.28,37,59,132,135,136,138,212,217 Posterior lenticonus or lentiglobus is a unilateral or bilateral and asymmetrical thinning and posterior bowing of the posterior lens capsule centrally or peripherally.121 This has variable effects on the adjacent lens cortex; opacification42 sometimes occurs, or it may manifest as a high degree of astigmatism (Fig. 13) that can be irregular but without cataract. More severe cases are associated with a progressive opacity of the lens lamellae in the abnormal area,42 sometimes with a dense discoid opacity of the posterior pole.29,215 It may be present at birth109,131,145,188 or progress in the first months of life,143 necessitating continued surveillance.

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Fig. 12. Left: Posterior lenticonus in retro-illumination showing the distortion in the red reflex. Right: Posterior lenticonus in direct and retro-illumination showing the oval defect in the posterior capsule and the multiple small opacities at the interface of the lens cortex and vitreous.

Amblyopia is frequently present,33,109 but vision may be improved by postoperative occlusion.42 Because there is a possibility that the visual defect is acquired, surgery may still be indicated even in cases where one might normally expect a poor visual result; visual results may be unexpectedly good, sometimes even better than in other causes of infantile or congenital cataract.156 Surgery consists of lens aspiration through an anterior capsulorrhexis. A posterior capsulorrhexis is usually performed with preservation of the vitreous face, but it may be preferable to carry out an anterior vitrectomy at the time of surgery; the surgery can also be performed through a pars plana approach.191 Intraocular lens insertion into the capsular bag is possible in most cases, as the rest of the capsule seems to be normal. The reason for the better prognosis relates to the fact that the rest of the eye is normal, as well as the relative severity of the visual effects of the cataracts itself, together with the timing of the visual defect. It is believed that the pathogenesis is due to a thinning of the posterior capsule.110,132,183,207,212,217,220 Some-

times the junction between the lenticonic and the adjacent capsule is sharply defined.132 Presumably, the cause of the cataract is largely mechanical;106 as the capsule bows posteriorly there is progressive distortion of the lens fibers themselves and cataract formation, which can be rapid. Sometimes there may be a hyaloid remnant attached to the lenticonic area.28,110,132 The significance of this is not certain, but it may be that the pathogenesis of these cases is different to the majority without a hyaloid remnant.179 Although sporadic cases may exist,42 many are inherited as an x-linked76,179,216 or autosomal dominant trait.15,28,76,95,160,179,216 Slit-lamp examination of relatives is therefore important. Autosomal recessive inheritance has also been suggested,160 but it is less clear. Posterior lenticonus has been associated with microcornea,15 hyperglycinuria,165 Duane’s syndrome,29 and anterior lentiplanus.48 3. Posterior Cortical Cataracts Nettleship and Ogilvie reported this abnormality in the Coppock family from Oxfordshire.150 They described a flat, sharply defined, circular disk lying between the nucleus and the posterior pole (Fig. 14), sometimes involving the posterior suture in a faint inverted Y. Their clinical assessment was without the benefit of a slit-lamp microscope and what they described was actually a central pulverulent cataract. Posterior cortical lens opacities were found in combination with anterior cortical opacities in the congenital retinal disinsertion syndrome,17 some of the lenses showed also a lens coloboma in the lower nasal quadrant. These opacities may be unilateral. 4. Posterior Subcapsular Cataracts

Fig. 13. Mild posterior lenticonus causing an abnormal red reflex and astigmatism.

Posterior subcapsular cataracts can be described as vacuolar or plaque opacities;60 the former being closer to the posterior capsule and the latter more cortical.

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Fig. 14. Posterior cortical cataract.

The major histopathologic change in the plaque type is the breakdown of the normally regular parallel rows of lens fibers into rounded globules. Plaque-like opacities may be seen in congenital cataract, myotonic dystrophies, and Turner’s syndrome.60 It is an important type of cataract, as it decreases visual acuity early due to its central or axial and posterior position. Posterior subcapsular opacities adhering to suture lines may be found in Fabry’s disease112 (Fig. 15), and are typical after trauma, which often leads to a swollen and very opaque lens,62 and later to a membranous after-cataract.56 Posterior subcapsular and cortical cataracts of presenile onset occur in neurofibromatosis type 2.164 E. PUNCTATE LENS OPACITIES

Punctate lens opacities are characterized by opaque dots scattered throughout the lens, quite different to the pulverulent type (Fig. 16). They vary in size, are most usually situated in the peripheral cortex,54 at the anterior and posterior poles,30 and they increase with age. They were thought to arise from excrescences of the capsule,98,104 but a subsequent study has failed to corroborate this.174 They occur in

Fig. 15. Posterior sutural cataract in a patient with Fabry disease.

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Fig. 16. Perinuclear punctate cataract shown as a semilunar row of white dots posterior to a clear nucleus. (Courtesy of Mr. J.J. Kanski.)

13–20% of patients with Down syndrome,10, 44 earlier studies suggested a lower prevalence,122 perhaps due to the examination techniques used, only the more significant opacities were included. Amiodarone may cause axial punctate opacities together with anterior subcapsular opacities.66 In carriers of Lowe syndrome, punctate grey-white opacities occur in all layers of the cortex, mainly in the equatorial region,61 but not in the nucleus,24,35,107,119 they increase in number with age, and, because these opacities may be found in the normal population, their numbers must be compared with age-matched controls. A slowly progressive form of this morphological type, which segregates as an autosomal dominant trait, has been described; linkage analysis revealed an alteration at 2q33-35 at the gamma crystallin cluster.202 They have also been reported to occur in 50% of patients with alopecia areata.166 F. SUTURAL CATARACTS

Opacities around or involving the sutures, more posterior than anterior, are very common, and not usually visually significant;205 they are often noted as an incidental finding in a routine examination.117 In general they are stationary, usually bilateral22,54 and familial. They may range from an increased density of the sutures to a variety of whitish or cerulean dots clustered around the sutures (Fig. 17), but may progress and form nuclear or central cataracts.9,101 When there is opacification of the anterior and posterior sutures, they are called stellate cataract.139 If all three sutures are affected equally, they are referred to as cataract triradiata.205 Sometimes, sutural cataracts are the only manifestation of involvement in asymptomatic relatives. They may be inherited as an autosomal dominant or x-linked recessive trait,22,101,115 and they have been found in the female carriers of Nance-Horan syndrome, with affected males presenting with total con-

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Fig. 17. Cataract of the Y-shaped sutures, more pronounced on two arms of the “Y.”

Fig. 19. Coralliform cataract.

genital cataracts.229 A mild sutural cataract was described in one eye of a Nance-Horan patient, whereas the other eye had a severe extensive cataract.13 They are rarely found in association with the sutures more peripheral to the Y sutures. Spaeth and Frost described patients with Fabry disease having a kind of shadow of wiggly spokes extending from the centre of the lens, appearing as narrow, slightly feathery white lines radiating from the posterior pole along the posterior capsule195 (Fig. 15). A central pouch-like cataract with sutural opacities in a large pedigree has been mapped to chromosome 15q21-22.214

mal arrangement of lens fibers. They are often visually insignificant, and can be inherited as an autosomal dominant trait.88,148,149,161 Crystalline congenital cataracts, with snowball-shaped clumps of crystals,22 are also arranged without reference to the normal architecture often in the most bizarre way.54,85

G. CORALLIFORM OR CRYSTALLINE CATARACTS

These rare opacities84 are usually static, central, complex cataracts that cut across normal anatomical boundaries, which are composed of multiple corallike65,84 white or cerulean opacities. They are arranged in a fusiform, or spindle-shaped fashion and may be mainly bilateral85 radiating out in an axial direction from the center of the lens never actually reaching the capsule (Figs. 18 and 19). The anatomical arrangement suggests that they may be due to a primary abnor-

Fig. 18. Coralliform cataract.

H. WEDGE-SHAPED CATARACTS

These opacifications occupy a sector of the lens, if they are larger they are known as semilunar (Fig. 20). They have been described in Conradi syndrome87 when it may represent an example of Lyonisation, Stickler syndrome75,187,196 and in neurofibromatosis type 2. In some cases of Fabry disease67 they appeared as fine whitish subcapsular granulations disposed in a wedge-shaped manner with the base at the equator. I. PERSISTENT HYPERPLASTIC PRIMARY VITREOUS

Persistent hyperplastic primary vitreous (PHPV) is an abnormality so often associated with congenital cataract that it must be considered in any discussion of congenital, especially unilateral, cataract management. In 1854 Mackenzie128 described the associa-

Fig. 20. Wedge-shaped cataract in a patient (Left) and his mother (Right).

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Fig. 21. Top left: Very mild PHPV plaque associated with a hyaloid vessel (not visible). Top right: Same patient in retroillumination. Bottom: Small PHPV with anterior hyaliod artery in retro-ilumination.

tion of congenital cataracts with PHPV and traction of the ciliary processes. Before the advent of vitreous cutting machines, the surgery was hazardous.37 It was first characterized in detail by Reese.167,168 It consists of a developmental abnormality of the primary vitreous and hyaloid vascular system. The eye is often microphthalmic. The cardinal features described by Goldberg in 1997,79 under the name of persistent fetal vasculature (PFV), include a persistent pupillary membrane, iridohyaloid blood vessels, persistence of the posterior fetal fibrovascular sheath of the lens, a Mittendorf dot, a persistent vasa hyaloidea propria and hyaloid artery, a Bergmeister’s papilla, congenital non-attachment of the retina, macular abnormalities, optic nerve hypoplasia and dysplasia, and malformations of the size and shape of the globe. There is a membrane of very variable extent and thickness behind, and usually inseparable from the lens that is attached via the apices of its scalloped margins to the ciliary processes. The membrane itself is relatively avascular, but there are usually vessels that pass to the ciliary processes and the iris, with the hyaloid vascular system present to a variable degree.125 The hyaloid vessels may be large but only very occasionally there is significant flow and leakage from this vessel may cause intralenticular haemorrhage116,129,130,213 (Figs. 21–24). The lens itself may be of a normal size which gives rise to a shallow anterior chamber as the retrolental

membrane shrinks and thrusts it forward; if this happens, it usually occurs in the first months of life and may be progressive, giving rise to glaucoma. The lens may spontaneously reabsorb,222 making the anterior chamber deeper, but the eye is still said to be at risk of dislocation of the ciliary body and hypotony if the membrane is very thick. PHPV was unusual in most congenital cataract surgical series,172 the poor visual prognosis justifiably led to conservative management. In one histopathologic series,86 58% were unilateral without associated ocular anomalies, 31% unilateral, with ocular anomalies, and 11% were bilateral with ocular or systemic abnormalities. Systemic disease is so rare in unilateral PHPV that routine investigation is unnecessary, but in bilateral cases isolated PHPV must be distinguished from the vitreoretinal dysplasias such as Norrie disease, Walker-Warburg syndrome,90 or others. In the past the main differential diagnosis was with retinoblastoma; now, with sophisticated ultrasound studies the hallmark of the scalloped-edged membrane and stretched ciliary processes in a micro-phalmic eye are recognized. The indications for surgery are threefold: first, to prevent the complications of glaucoma and hypotony, second for cosmesis, and third for vision. It is known that, if treated as any other axial media opacity in an infant, the visual prognosis may be sufficiently good108 to warrant the arduous optical cor-

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Fig. 22. Left: PHPV retrolental membrane, cataract and multiple blood vessels between the plaque and the ciliary body. Right: Same patient with cataract removed. There is an anterior capsulectomy shown as an approximately oval line.

rection and occlusion regime that is the same as that for unilateral congenital cataract. Early surgery and amblyopia therapy is mandatory and the visual results are probably better in the milder cases. The surgery consists of removal of the lens and membrane with a vitrectomy machine,159,186,199,200,201 but the more extensive membranes require intraocular scissors, and some advocate the use of intraocular diathermy. It is important to avoid cutting the ciliary processes and to remove all of the membrane. If this is not possible, the surgeon must make sure that a ring of membrane is not left behind. Surgical complications have been described.45 There are no accurate figures, but it is highly likely that glaucoma, hemorrhage, and retinal detachment are significantly more frequent than in uncomplicated cataract surgery; the parents should be counseled accordingly. In some cases early surgery may carry a higher risk of secondary glaucoma than conservative management. High frequency ultrasound examination may help plan the best entry site and has revealed evidence of thickened anterior hyaloid face

playing a role in the formation of the retrolental membrane.127 Intraocular lenses have been used,93 but except in the mildest cases, the added risks due to the PHPV itself make optical correction with contact lenses the best approach. Spectacles may be used when the child is being occluded but many older infants object strongly to this treatment.

What happens to untreated congenital cataracts? The growing cortex alters the shape of central cataracts25 in that they are compacted at a decreasing rate with increasing age, with the result that the eye remains emmetropic despite changes in many of the parameters that determine refraction.80 Many cataracts change so little with time that they can be managed conservatively,41,42,50,51,71 and never require treatment. Often, in lamellar cataracts, the child is able to go through a normal education, perhaps with a little extra help, and it is the desire to obtain a drivers license that brings about the surgery. Some cataracts

Fig. 23. Severe PHPV with central dense core, largely reabsorbed lens, and vascular connection between the plaque and the iris.

Fig. 24. Dense PHPV with partially reabsorbed lens and stretched ciliary processes.

IV. The Untreated State

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progress rapidly; for instance, untreated galactosaemic oil-drop opacities become lamellar-like cataracts, but if medically treated, some of these cataracts may disappear,8,26,38,82,169 or at least fail to progress.27,89,224 Monitoring of galactosemia dietary control by observation of the cataracts has been suggested.8 Many progress very slowly: so slowly that serial visual function measurements need to be made to be sure that the apparent deterioration is not related to the behavior and performance of the child. Amplitude of accommodation may be reduced in central cataracts over 3 mm in diameter due to changes in the shape of the cataract during accommodation.96 In a small proportion of untreated cataracts spontaneous reabsorption takes place16,57,63,74,77,83,128,176,181, 192,194,204,206,211,222,225,228 due to leakage of lens material, degeneration, liquefaction and absorption, leaving behind the fused capsular bag with a variable amount of residual lens matter, looking biscuitshaped, with white flecks deposited inside the shriveled capsular bag.192 The vision in late or untreated congenital cataracts is very poor because of profound deprivation ambyopia,41 unless there has been some period of visual experience in early life; examples of this today are few in developed countries. Fisher64 summarized the literature on the vision of 16 cases recorded from the year 1728 who were born blind with congenital cataract and acquired vision later in life (between 7 and 46 years). The poor visual performance despite optical correction is presumably a manifestation of the profound amblyopia affecting these people.

V. Method of Literature Search The majority of the references cited were extracted from the Reference Manager database of infantile cataracts of Mr. David Taylor. The database contains a selection of the relevant literature related to cataracts in childhood and infancy covering more than 100 years (since 1892). Some articles related to genetic mapping were extracted via Medline and Embase and reviewed. References 152, 153, 154, and 189 have been extracted from the OMIM (Online Mendelian Inheritance in man) records. Although the majority of the literature reviewed was in English language, some French and German articles have been referenced. The German language papers were studied by one of the authors (Dora Lengyel). Other languages have not been included. Some additional references have been included as indicated by the Editorial Office of Survey of Ophthalmology.

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Outline I. Introduction II. Lens embryology and growth III. Heterogeneity, specific morphological types, and the effect of morphology on visual prognosis A. Cataracts involving the whole lens 1. Total cataracts 2. Congenital morgagnian cataracts 3. Disk-like and membranous cataracts B. Central cataracts 1. Lamellar or zonular cataracts 2. Central pulverulent cataracts 3. “Ant egg” cataracts 4. Nuclear cataracts 5. Oil drop cataracts 6. Cortical cataracts 7. Cerulean, floriform, or coronary cataracts C. Anterior cataracts 1. Anterior polar cataracts a. Dot-like anterior cataracts b. Plaque-like anterior cataracts c. Anterior pyramidal cataracts 2. Anterior subcapsular cataracts 3. Anterior lenticonus D. Posterior cataracts 1. Mittendorf’s dot 2. Posterior lenticonus 3. Posterior cortical cataracts 4. Posterior subcapsular cataracts E. Punctate lens opacities F. Sutural cataracts G. Coralliform or crystalline cataracts H. Wedge-shaped cataracts I. Persistent hyperplastic primary vitreous IV. The untreated state V. Method of literature search

Work on this article has been supported by The Ulverscroft Foundation and The Iris Fund. The authors reported no proprietary or commercial interest in any product mentioned or concept discussed in this article. Reprint address: David Taylor, FRCS, FRCP, FRCOphth, Consultant Paediatric Ophthalmologist, Dept. of Ophthalmology, Great Ormond Street Hospital for Children, London, WC1N 3JH, United Kingdom.