Ocular Dysgenesis

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Syndromes of ocular dysgenesis are summarized in Table 1-2.

Microphthalmia

Studies of ocular malformations induced by teratogen exposure have been helpful in identifying sensitive periods during development. Microphthalmia and anophthalmia may result from insult at a number of developmental stages. Acute exposure to teratogens during early gastrulation stages results in an overall deficiency of the neural plate with subsequent reduction in size of the optic vesicle. This aberration results in microphthalmia, which may be associated with a spectrum of secondary malformations including anterior segment dysgenesis, cataract, and PHPV.24,27,28 Deficiency in size of the globe as a whole is often associated with a corresponding small palpebral fissure. Because the fissure size is determined by the size of the optic vesicle (most likely during its contact with the surface ectoderm), support is provided for a malformation sequence beginning at the time of formation of the optic sulcus or optic vesicle.

Failure or late closure of the optic fissure prevents the establishment of normal fetal IOP and can result in microphthalmia associated with colobomas, that is, colobomatous microph-thalmia (Fig. 1-27). This syndrome may be associated with orbital (or eyelid) cysts (Fig. 1-28). It is important to recognize that delay in closure of the fissure during a critical growth period may result in inadequate globe expansion. However, if the fissure eventually closes, it may be difficult to distinguish between colobomatous and noncolobomatous microphthalmia. In colobomatous microphthalmia, the optic vesicle size is initially normal and a normal-sized palpebral fissure would be expected, whereas with microphthalmia that results from a primary abnormality in the neural plate and optic sulci, the palpebral fissure would be small.

Optic Fissure Closure Anomalies (Coloboma)

Colobomas represent an absence of tissue that may occur through abnormal fusion of the optic fissure, which normally closes at 4 to 5 weeks gestation. Colobomas may occur anywhere along the optic fissure and can affect the iris, choroid,

handbook of pediatric neuro-ophthalmology

TABLE 1-2. Summary of Syndromes of Ocular Malformations.

Syndrome

Microphthalmia

Anterior segment dysgenesis

Ocular coloboma

Meckel's

Uveal

Rubenstein-Taybi

Basal cell nevus syndrome

Cat's eye

Axenfeld-Rieger's Autosomal dominant iridogoniodysgenesis

Gonio-dysgenesis

Nail patella

Branchiootorenal

Iris hypoplasia Ciliary body hypoplasia

Microphthalmia

Glaucoma

CHARGE

Cataract

TABLE 1-2.

(continued)

Other ocular

Nonocular

Genetics

Genetics

abnormalities

anomalies

(mice)

(human)

Choanal atresia

+/- X-linked

Growth retardation

autosomal

Genital hypoplasia

recessive

Ear anomalies

(deafness)

Hypospadias

Heart defect

Autosomal

Renal/hepatic

recessive

disease

condition

Occipital

mapped to

encephaloceles

chromosome

Microcephaly

17q21-q24

Hydrocephaly

Cleft palate

Cataract

Ptosis

Mental retardation

Translocation

Broad fingers

involving

and toes

chromosome

Short stature

2p13.3 and

Cardiac anomalies

16p13.3

Renal anomalies

Strabismus

Hypertelorism

CECR1on

Cataract

Basal cell nevus

9q22.3-q31

Cleft lip/palate

Mental retardation

Anal atresia

22q11

Preauricular

skin tags

Renal anomalies

Iris

Craniofacial

FoxCl

FKHL7 gene

hypoplasia

Dental

FoxC2

6p24-p25

defects

Mfl (mice)

Hypertelorism

LmxlB

Chromosome 9

Branchial arch

EYA1

anomalies

Ear anomalies

Renal

anomalies

17 Ccnf

16p13.3

14q32

Anterior

Craniofacial

Cat4a on

RIEG1 on

lenticonus;

Heart defects

chromosome

chromosome

cataract

Dwarfism

8

4q25

Syndactyly

(continued)

TABLE 1-2. Summary of Syndromes of Ocular Malformations.

(continued)

Anterior segment Ocular

Syndrome Microphthalmia dysgenesis coloboma Glaucoma

Renal/coloboma Optic disc coloboma

procecephaly

Leber's congenital amaurosis

Septooptic dysplasia

Rieger's anterior +

segment dysgenesis

Goldenhar's + Upper lid oculoauriculovertebral coloboma

Source: NIH Online Mendelian Inheritance in Man: www3.ncbi.nlm.nih.gov/

macula, and optic nerve (Figs. 1-21, 1-22, 1-23). Colobomas are often associated with microphthalmia (colobomatous microphthalmia) or, less frequently, orbital or eyelid cysts (Fig. 1-22). Because the optic fissure closes first at the equator of the eye, and then in a posterior and anterior direction, colobomas are most frequently found at the two ends of the optic fissure, that is, iris and optic nerve. When the optic nerve is involved in the coloboma, vision is usually affected, in some cases causing blindness. Optic nerve colobomas may be associated with basal encephaloceles, which also represent a failure of fissure closure.59,85 Large choroidal colobomas may be associated with posterior pole staphylomas, causing macular disruption and poor vision. Occasionally, a line of choroidal colobomas occur along the fetal fissure area with skip areas (Fig. 1-23). Isolated iris colobomas usually do not affect visual acuity unless there is an associated refractive error. Typical iris colobomas occur infer-

TABLE 1-2.

(continued)

Other ocular

Nonocular

Genetics

Genetics

abnormalities

anomalies

(mice)

(human)

Renal

19 Pax2

PAX2 on

anomalies

10q24.3-q25.1

Cyclopia

Holopro-

Sonic hedgehog

cencephaly

(SHH) on 7q36

HPE12on 1q22.3

Cataract

Central

3 Rpe65

CRX

pigmentary

blindness

Autosomal

retinopathy

Mental

recessive

Keratoconus

retardation

RPE65 on 1p31

Optic disc

Growth

14Hesx1

Autosomal

hypoplasia

hormone

recessive HESX1

deficiency

on 3p21.1-

3p21.2

Cataract ±

Fra-2

Autosomal

Corneal

dominant 4q28-

opacity

q31(PAX6), PITX3

on 10q25

Cataract

Wilm's tumor

2Sey

Autosomal

Foveal

dominant

hypoplasia

PAX6 on 11p13

Epibulbar

Ear malformations

Autosomal

dermoid

Facial asymmetry

dominant

Vertebral anomalies

GHS on 7p

onasally along the location of the optic fissure whereas atypical iris colobomas are not associated with abnormal fissure closure and can occur elsewhere. Atypical iris colobomas usually have an intact iris root (Fig. 1-24).

Differentiation of choroidal and iris stroma is determined by the adjacent structures of the optic cup: the iris epithelium, anteriorly, and the future retinal pigment epithelium, posteriorly. In animals exhibiting primary abnormalities in differentiation of the outer layer of the optic cup, anterior and posterior segment colobomas are seen in a very specific distribution associated with the iris epithelium or RPE defects,25,26 and this is the most likely explanation for atypical uveal colobomas. The term lens coloboma is actually a misnomer, as this defect results from a lack of the zonular pull in the region of the coloboma rather than regional hypoplasia of the lens. Ciliary body colobomas are often associated with abnormal lens shape or subluxation or both.

Colobomatous Microphthalmia

FIGURE 1-21A-C. (A) Photograph of patient with left colobomatous microphthalmia and normal right eye. (B) Slit lamp view of the iris coloboma left eye. Note the pigment on anterior capsule of the lens. (C) Optic nerve coloboma of left eye with inferior choroidal coloboma that extended anteriorly to meet the iris coloboma seen in (B).

FIGURE 1-21A-C. (A) Photograph of patient with left colobomatous microphthalmia and normal right eye. (B) Slit lamp view of the iris coloboma left eye. Note the pigment on anterior capsule of the lens. (C) Optic nerve coloboma of left eye with inferior choroidal coloboma that extended anteriorly to meet the iris coloboma seen in (B).

Colobomatous microphthalmia with eyelid cyst syndrome may be unilateral or bilateral (see Fig. 1-28). Colobomatous cysts form from the inner layer (neuroectoderm) of the optic cup as it grows out of the persistent opening of the optic fissure. The lower lid cyst contains primitive vitreous contents that were not enclosed within the eye because the optic fissure did not close. The cyst has a stalk that connects to the microphthalmic eye. For those who are unaware of the syndrome, the lid cyst is often mistaken as an abnormal eye located in the lid.

Dermoids and Dermolipomas

Dermoids are choristomas (histologically normal tissue in an abnormal location) and are thought to represent arrest or inclusions of epidermal and connective tissues (surface ectoderm and neural crest cells). They may be associated with abnormal closure of the optic fissure. This collection of epidermal and connective tissue can occur at the limbus (limbal dermoid), in the conjunctiva (dermolipoma), and subcutaneously in and around the orbit. The most common location of subcutaneous periorbital dermoid cysts is the superotemporal and superonasal quadrants of the orbital rim. These dermoids are usually found attached to bone, associated with a cranial suture.

Limbal dermoids are similar to subcutaneous dermoid cysts and consist of epidermal tissue and, frequently, hair (Fig. 1-25). Corneal astigmatism is common in patients with limbal dermoids. Astigmatisms greater than +1.50 are usually associated with meridional and anisometropic amblyopia. Removal of limbal dermoids is often indicated for functional and cosmetic reasons, but the patient should be warned that a secondary scar can recur over this area. Limbal dermoids can involve deep corneal stroma, so the surgeon must take care to avoid perforation into the anterior chamber.

Dermolipomas (lipodermoids) are usually located in the lateral canthal area and consist of fatty fibrous tissue (Fig. 1-26). They are almost never a functional or cosmetic problem and are best left alone. If removal is necessary, only a limited dissection should be performed to avoid symblepharon and scarring of the lateral rectus. Unfortunately, restrictive strabismus with limited adduction frequently occurs after removal of temporal dermolipomas.

Lipodermoids The Eye

FIGURE 1-22A-B. (A) Photograph of 6-month-old with colobomatous microphthalmia and orbital cyst anomaly. Note the left lower eyelid cyst causing a mass in the lower lid, left blepharophimosis (small lids and narrow lid fissure), and apparently normal right eye. (B) Desmarres retractors open the eyelids in an attempt to expose the microphthalmic left eye. The only remnant of eye that could be seen externally was a small dimple just nasal to the lid retractors.

FIGURE 1-22A-B. (A) Photograph of 6-month-old with colobomatous microphthalmia and orbital cyst anomaly. Note the left lower eyelid cyst causing a mass in the lower lid, left blepharophimosis (small lids and narrow lid fissure), and apparently normal right eye. (B) Desmarres retractors open the eyelids in an attempt to expose the microphthalmic left eye. The only remnant of eye that could be seen externally was a small dimple just nasal to the lid retractors.

Optic Nerve Colobomas Scan

FIGURE 1-22C-D. (C) CT scan shows the presence of a left microph-thalmic eye, left lower lid cyst, and right optic nerve coloboma. At the time of surgery to remove the cyst, a stalk was found connecting the cyst to the microphthalmic eye. (D) Fundus photograph of optic nerve, right eye (good eye). Note the presence of a large optic nerve coloboma. This was an isolated optic nerve coloboma; the right eye was otherwise normal.

FIGURE 1-22C-D. (C) CT scan shows the presence of a left microph-thalmic eye, left lower lid cyst, and right optic nerve coloboma. At the time of surgery to remove the cyst, a stalk was found connecting the cyst to the microphthalmic eye. (D) Fundus photograph of optic nerve, right eye (good eye). Note the presence of a large optic nerve coloboma. This was an isolated optic nerve coloboma; the right eye was otherwise normal.

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Dyscoria Corectopia

FIGURE 1-23A,B. Patient with iris (A) and choroidal and optic nerve (B) colobomas in typical inferior location. Note the choroidal skip lesion inferior to the disc.

Syndactyly Surgery Pictures

FIGURE 1-24. Photograph of ectropion uvea caused by peripheral anterior stromal membrane pulling the pupillary margin forward, exposing posterior pigment epithelium. Note there is an associated corectopia and dyscoria. The appearance of the eccentric pupil could be classified as an atypical iris coloboma. This is not a true coloboma because of the location and the presence of an intact iris root.

FIGURE 1-24. Photograph of ectropion uvea caused by peripheral anterior stromal membrane pulling the pupillary margin forward, exposing posterior pigment epithelium. Note there is an associated corectopia and dyscoria. The appearance of the eccentric pupil could be classified as an atypical iris coloboma. This is not a true coloboma because of the location and the presence of an intact iris root.

Lateral Canthus Dermoid

FIGURE 1-25. Isolated limbal dermoid at inferotemporal limbus, right eye. Hair cilia emanates from the center of the lesion. These limbal dermoids are often associated with large astigmatisms and can cause astigmatic, anisometropic amblyopia.

Strabismus Fat Adherence
FIGURE 1-26. Dermolipoma in lateral canthal area, right eye. These are benign; however, if removed, can cause restrictive strabismus and fat adherence syndrome.

Goldenhar's syndrome (oculoauriculovertebral dysplasia) is a clefting anomaly of the first brachial arch and is associated with neural crest cell abnormalities. Goldenhar's syndrome is characterized by the combination of epibulbar dermoids (der-molipomas and limbal dermoids), ocular coloboma (Fig. 1-27), incomplete cryptophthalmos or lid colobomas, preauricular skin tags, vertebral anomalies, and, sporadically, with heart and pulmonary defects.

Cryptophthalmos

Cryptophthalmos is a congenital failure of lid and eye separation and development. In most cases, cryptophthalmos is inherited as an autosomal recessive trait, which may include mental retardation, cleft lip or palate, cardiac anomalies, or genitourinary abnormalities. The eyelids may be colobomatous, with the colobomatous lid fusing with the peripheral cornea or conjunctiva (incomplete cryptophthalmos; Fig. 1-27). Complete cryptophthalmos is a total absence of normal eyelids and lid fold, with the eye covered by skin that is adherent to an abnormal cornea. The cornea is often thin, being replaced by a

Cryptophthalmos

FIGURE 1-27A,B. (A) Photograph of a patient with Goldenhar's syndrome and incomplete cryptophthalmos of left eye. Cryptophthalmos consists of fusion of the upper lid to the cornea of the left eye. In addition to cryptophthalmos, patient has bilateral upper lid colobomas and left inferior limbal dermoid. (B) Close-up view of the left eye shows upper lid coloboma and cryptophthalmos with upper lid adhesion to the cornea and conjunctiva and inferior dermoid cyst.

fibrovascular tissue rather than clear cornea. The anterior segment is often abnormal, having a small or absent lens and anomalies of the iris or ciliary body. When associated with microphthalmia and anterior segment dysgenesis, this developmental abnormality is initiated at the optic vesicle stage with secondary effects on neural crest and surface ectoderm. In the rare cases where the globe and anterior segment are normal, cryptophthalmos could be caused by an abnormality in surface ectoderm.

Cornea Plana

Cornea plana is a failure of the cornea to steepen relative to the curvature of the globe and normally occurs between the third and fourth month of gestation. This failure to steepen results in a relatively flat cornea. Cornea plana can be associated with other anterior segment anomalies (Fig. 1-28) or inherited as an autosomal dominant or recessive trait.

Sclerocornea

Sclerocornea is a condition in which the junction between the cornea and sclera is indistinct. Additionally, the cornea appears

Anterior Chamber Dysgenesis

FIGURE 1-28. Photograph of congenital corneal opacity involving the temporal half of the cornea. Handheld slit lamp examination revealed iris strands to the cornea, flat peripheral cornea, and a blending of sclera and cornea in the periphery. The diagnosis is anterior chamber dysgenesis syndrome, including sclerocornea, cornea plana, and Peter's anomaly.

FIGURE 1-28. Photograph of congenital corneal opacity involving the temporal half of the cornea. Handheld slit lamp examination revealed iris strands to the cornea, flat peripheral cornea, and a blending of sclera and cornea in the periphery. The diagnosis is anterior chamber dysgenesis syndrome, including sclerocornea, cornea plana, and Peter's anomaly.

to be relatively small, as the limbal cornea is replaced by a mixture of cornea and scleral tissue.67 Sclerocornea may be associated with other anomalies such as microphthalmia, coloboma, and anterior chamber dysgenesis (Fig. 1-28).

Anterior Segment Dysgenesis

Human anterior segment dysgenesis encompasses a broad spectrum of malformations including posterior embryotoxon, anterior displacement of Schwalbe's line, Axenfeld's anomaly (anterior displacement of Schwalbe's line associated with peripheral iris strands to Schwalbe's line), Peters' anomaly (central corneal opacity with absence of Descemet's membrane and endothelium in the area of the opacity), Rieger's anomaly (iris stromal hypoplasia with pseudopolycoria and iridocorneal attachments), or other combinations of iridocorneal or iridolen-ticular adhesions associated with various anterior segment anomalies. Congenital glaucoma is frequently associated with anterior segment dysgenesis syndromes.

Because most of the structures of the ocular anterior segment are of neural crest origin, it is tempting to incriminate this population of cells as being abnormal in differentiation or migration in cases of anterior segment dysgenesis. This theory has received widespread support and has resulted in labeling these conditions as "ocular neurocristopathie," particularly when other anomalies exist in tissues that are largely derived from neural crest cells (e.g., Rieger's syndrome; craniofacial connective tissue and teeth). There are several arguments in opposition to this theory. First, the neural crest is a predominant cell population of the developing craniofacial region including the eye. In fact, the number of tissues that are not neural crest derived is smaller than those which are (see Table 1-1). Thus, most malformations of this region would be expected to involve neural crest tissues, which may reflect their ubiquitous distribution rather than their common origin. The normal development of the choroid and sclera (also of neural crest origin) in anterior segment dysgenesis argues against a primary neural crest anomaly. Second, the neural crest is an actively migrating population of cells that is influenced by adjacent cell populations, and the perceived anomaly of neural crest tissue may be a secondary effect in many cases.

It is also important to recognize that, although much of the maturation of the iridocorneal angle occurs during the third trimester, much earlier events may influence anterior segment development. Anterior segment dysgenesis syndromes that are characterized primarily by axial deficits in corneal stroma and endothelium accompanied by corresponding malformations in the anterior lens capsule and epithelium (Peters' anomaly) most likely represent a manifestation of abnormal keratolenticular separation. The spectrum of malformations included in Peters' anomaly can be induced by teratogen exposure in mice at a time corresponding to the third week postfertilization in the human, just before optic sulcus invagination. Alternative theories for the pathogenic mechanism leading to Peters' anomaly, namely, intrauterine infection or anterior displacement of the lens or iris diaphragm, fail to explain the relatively localized axial defects.

Other anterior segment dysgenesis syndromes are characterized by more peripheral iridocorneal angle malformations and may represent malformations that are initiated somewhat later in gestation. These syndromes are often accompanied by absent or abnormal lining of Schlemm's canal, which is of mesodermal origin. In posterior polymorphous dystrophy and iridocorneal endothelial syndromes, the primary anomalies appear to be associated with the corneal endothelium and its basement membrane, both neural crest derivatives. Abnormal-appearing collagen within the trabecular meshwork has been identified in all these syndromes. Its significance is unknown; however, it may relate to neural crest abnormality.

Gene mutations that affect ocular neural crest cell populations and result in anterior segment dysgenesis have been identified. Of particular note is a genetic form of Rieger's syndrome caused by mutation in a homeobox transcription factor, PITX2.3 In-situ hybridization in mice has shown that mRNA encoded by this gene is localized in the periocular mesenchyme.

Congenital Glaucoma

Although glaucoma may accompany any of the anterior segment syndromes described previously, elevated intraocular pressure (IOP) is usually not present at birth, in contrast to true congenital glaucoma. Earlier theories described the gonioscopic presence of a "Barkan's membrane" covering the trabecular meshwork in eyes with congenital glaucoma. Most histological examinations of affected eyes have failed to demonstrate such a membrane. Studies have revealed anterior displacement of the ciliary body and iris base, representing the immature conformation seen in fetuses during the second trimester. In the absence of other malformations, these cases of congenital (and juvenile) glaucoma most likely represent arrested maturation and remodeling of the iridocorneal angle, which occur during the last trimester.

Pupillary Anomalies

Corectopia is defined as an eccentric location of the pupil, which may be normal or malformed (Fig. 1-29). The pupil may have an abnormal shape (dyscoria) and not be in line with the lens. Corectopia may be associated with corresponding ectopia of the lens that may or may not be in line with the ectopic pupil. Colobomas can be mistaken as eccentric pupils, but true colobo-mas lack peripheral iris whereas corectopia has an intact peripheral iris. Ectopia lentis et pupillae is the eccentric location of both the lens and pupil, which may be eccentric together and in line or, more commonly, displaced in opposite directions (Fig. 1-29).

Polycoria is a condition in which there are many openings in the iris that result from local hypoplasia of the iris stroma and pigment epithelium. True polycoria actually is a condition in which there is more than one pupil and the multiple pupils all have a sphincter and the ability to contract. Most cases of

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