Between days 24 and 26, the surface ectoderm adjacent to the optic vesicle thickens, forming the lens plate (placode). The lens placode invaginates to form the lens vesicle, which has a hollow center, between days 32 and 33 (Fig. 53.1). The lens vesicle consists of a single layer of cells whose apices are directed toward the center. After the lens vesicle has detached from the surface ectoderm, it is surrounded by a basal lamina, which will become the lens capsule.

Primary aphakia results when the lens plate is absent.² A lens that forms but subsequently degenerates and largely disappears leads to secondary aphakia.² If the lens plate forms normally, cuboidal cells line the anterior part of the lens vesicle. The posterior portion of the vesicle is lined by columnar cells that form the primary fibers. These fibers fill the lens vesicle, obliterating its cavity and creating an arc across the lens anterior to the equator. The anterior lens epithelial cells remain cuboidal and become the permanent lens epithelium that, through mitosis, gives rise to future cortical lens fibers later in life.

By the seventh week of development, secondary fibers begin to proliferate in both directions from the equatorial region of the lens. The secondary fibers interlace anteriorly to produce an upright Y suture and posteriorly to produce an inverted Y suture. The lens continues to grow throughout a person’s life through the proliferation of secondary lens fibers. As the fibers are laid down, the different optical densities of the fibers produce four zones of discontinuity that can be observed clinically with a slit lamp:

Abnormalities of the lens that occur during the stage of differentiation include alterations in size (e.g., microspherophakia), in shape (e.g., anterior and posterior lenticonus), and in the lens fibers themselves (e.g., developmental cataracts).

The developing lens receives its blood supply from multiple branches of the hyaloid artery. These cover the anterior and posterior aspect of the lens and anastomose with vessels within the mesenchyme tissue that covers the lens, forming the pupillary membrane. This hyaloidal vascular system is called the tunica vasculosa lentis. Its greatest development occurs at 9 weeks’ gestation, starts to regress by the end of the third month, and is usually complete by the eighth month. Failure of this system to regress leads to a persistent pupillary membrane. A Mittendorf dot is also a failure of complete regression and represents that part of the hyaloid artery that attached to the posterior lens capsule.

When the optic vesicle collapses, the neural ectoderm folds onto itself to produce the optic cup, which has a double layer of neural ectoderm. The optic cup will differentiate into the neurosensory retina (inner layer of neural ectoderm) and retinal pigment epithelium (outer layer). Further development of the sensory retina may be divided into four stages of progressive differentiation: the initial differentiation into zones, the organization into temporary layers, the migration and differentiation of cells, and the final organization of layers. Disorganized differentiation may result in the histologic picture of retinal dysplasia.³

The primary vitreous forms between the inner layer of the optic cup and the developing lens at approximately 6 weeks. The secondary vitreous is derived from the retina and surrounds the primary vitreous. It is composed of very fine, densely packed fibrils that are arranged in an orderly manner at right angles to the retinal surface. Condensation of the fibrils forms the walls of the canal of Cloquet, which is a conduit for the hyaloid artery. The hyaloid artery supplies the vascular network surrounding the lens. At the end of the third month, the hyaloid artery atrophies and retracts with the primary vitreous to form a narrow and constricted zone in the central vitreous cavity (Figs. 53.2 and 53.3). The atrophy begins centrally and proceeds anteriorly and posteriorly. Incomplete atrophy may result in anterior hyaloid remnants associated with the lens or in posterior remnants associated with the optic nerve head. An example of an anterior remnant is the Mittendorf dot. Bergmeister papilla may be considered a posterior remnant of the hyaloid system.

The third period of vitreous formation begins at the end of the third month. The tertiary vitreous begins as an accumulation of collagen fibers between the equator of the lens and the optic cup; it will eventually differentiate into the vitreous base and lens zonules.

The sclera is derived from tissue of neural crest origin. Most of the cornea is derived from the same mesenchymal tissue with the exception of the corneal epithelium, which is derived from surface ectoderm. The anterior sclera forms first as a condensation of this tissue and is continuous with the cornea. Condensation proceeds posteriorly until the twelfth week of development, at which time the sclera surrounds the optic nerve.

The lens vesicle detaches from the overlying surface ectoderm during the sixth week of gestation. During the seventh week, a single layer of neural crest cells invades the region between the surface ectoderm and the lens vesicle. This single layer of cells will differentiate into the corneal endothelium. A second wave of neural crest cells migrates between the primitive endothelium and surface ectoderm to form fibroblasts. These fibroblasts will eventually differentiate into keratoblasts that will produce the collagen fibrils and extracellular matrix of the corneal stroma.⁴ Initially, these neural crest cells occupy the space that will become the anterior chamber. They are the precursor cells that will develop into the corneal stroma, corneal endothelium, anterior iris stroma, and many of the structures of the iridocorneal angle. The surface ectoderm will give rise to the corneal epithelium. The anterior chamber is formed when these neural crest cells separate from the tunica vasculosa lentis and pupillary membrane, which overlie the anterior lens surface. Therefore, the anterior chamber is derived almost entirely from neural crest cells, not mesoderm, as was once believed. The vascular endothelium is now thought to be the only component of the anterior segment that is derived from mesoderm.

The corneal epithelium is derived from surface ectoderm, whereas the remainder of the cornea is derived from neural crest cells, as described previously. The corneal stroma gives rise to the Bowman membrane. Therefore, the Bowman membrane is of neural crest origin, and is a condensation of anterior corneal stroma. It is not the basement membrane of the corneal epithelium and is not derived from the same precursor cells. The Descemet membrane is present by the sixth month of gestation, and the cornea begins to become transparent at about this time.

During the third month of development, the anterior rim of the optic cup, which is composed of neural ectoderm, begins growing rapidly in a curve around the anterior surface of the lens. The iris pigmented and nonpigmented epithelium will develop from this anterior advancing edge of the optic cup. The iris sphincter and dilator muscles develop from these epithelial layers and are the only muscles of the body that are derived from neural ectoderm. The inner epithelial layer begins to develop folds, which are the early ciliary processes. The ciliary body epithelium also develops from the anterior portion of the optic cup. The tertiary vitreous forms from an extracellular matrix that is produced by the ciliary epithelium and will eventually become the lens zonules. The iris stroma develops from the neural crest cells, which migrate between the lens vesicle and surface ectoderm.

Traditionally, the study of the development of the anterior chamber and angle has concentrated on the role of mesenchyme. It is now known that neural crest cells are the major contributor to the development of these structures. There continues to be some controversy, however, regarding the mechanism by which the angle is formed. There are conflicting opinions as to whether the angle structures are formed as a result of simple cleavage of the iris root from the cornea, or whether a more active growth process is required for normal angle development.

The optic nerve develops within the substance of the optic stalk. The nerve fibers of the developing optic nerve are composed of axons of the ganglion cells in the retina. The nerve fibers completely fill the optic stalk by the end of the seventh week. Myelination of the nerve fibers starts at the chiasm at about 7 months and progresses anteriorly toward the eye. Myelination normally stops at the lamina cribrosa approximately 1 month after birth. Myelinated nerve fibers occur if the myelination process continues past the lamina and most likely represents ectopic myelination, not a structural defect in the lamina cribrosa.

The eyelids develop from both surface ectoderm and neural crest cells. Surface ectoderm gives rise to the epidermis, cilia, and conjunctival epithelium, whereas the deeper structures of the lids, including the dermis and tarsus, are derived from neural crest cells. The orbicularis and levator muscles develop from mesoderm. The eyelids begin to form by 6 weeks and grow to cover the eye. The upper and lower folds fuse at approximately 12 weeks and gradually start to separate at 6 months’ gestation.

The lacrimal apparatus is formed by contributions from the lateral nasal and maxillary processes as well as from the lids. During the third month, the lacrimal canaliculus is formed by the lysis of a central core of cells. The lacrimal punctum opens onto the lid margin just before the lids separate, usually during the seventh month. The lower end of the nasolacrimal duct frequently is separated from the cavity of the inferior meatus at birth by a membrane. This membrane consists of the opposed mucosal linings of the nasal fossa and the lower end of the duct. Obstruction of the nasolacrimal duct usually is caused by defective canalization or persistence of the nasal mucosal membrane.⁵

Pure microphthalmos, also called nanophthalmos, refers to a small eye containing a lens of “normal” volume. It is thought to result from an arrest in ocular development after the fetal fissure has closed. The eye is small in its overall dimensions, but shows no other gross defects. Because the size of the lens is normal, patients with nanophthalmic eyes have a shallow anterior chamber and pronounced hypermetropia (more than 10 diopters). Therefore, these eyes are prone to attacks of angle-closure glaucoma.¹⁹ Thickening of the sclera around the exits of the vortex veins may contribute to retinal and choroidal effusion.^20,21 Scleral thickening is a result of the abnormal interlacing of the scleral fibers, which may be secondary to abnormal glycosaminoglycan metabolism.^22,23 Histopathologic evaluation of the sclera in nanophthalmos has demonstrated abnormal collagen fibrils that were frayed, split, and contained lightly stained cores.²⁴ In early life, the visual acuity is usually normal, although macular hypoplasia may account for poor vision in some younger patients. Poor vision later in life is often due to the secondary complications of this disorder. Nanophthalmos is generally bilateral, and these eyes are usually deeply set in shallow orbits.

Most affected individuals are members of pedigrees that demonstrate consanguinity. The mode of inheritance, therefore, is presumed to be autosomal recessive. Only a few pedigrees compatible with autosomal-dominant inheritance have been reported.²⁵

Simple microphthalmos is the term used to describe a small eye that is otherwise normal. Approximately 50% of patients with simple microphthalmos have an associated systemic developmental abnormality. These eyes have a short axial length and are therefore moderately hyperopic. The level of hyperopia is less than that seen in nanophthalmos (usually less than +10.00 diopters).²⁶ Most patients have normal vision. The complications that are seen with nanophthalmos do not occur in this disorder.

Most cases of simple microphthalmos are sporadic and occur bilaterally. Simple microphthalmos represents a retardation in growth that occurs once the primary optic vesicle has formed and invaginated. It has been caused in animal experiments by radiation, mechanical stimulation, and chemicals. It also may be associated with systemic disorders, such as fetal alcohol syndrome, myotonic dystrophy, and achondroplasia.

The term complex microphthalmos denotes a small, deformed eye. One or more malformations may occur as an isolated ocular entity or as part of an associated systemic disorder. Associated ocular deformities can include anterior segment maldevelopment, hyperplastic primary vitreous, and other abnormalities of the lens, vitreous, or retina. Complex microphthalmos may be unilateral or bilateral, and the vision can range from normal to no light perception, depending on the severity of the associated defects. Both sporadic and hereditary forms are known.

Microphthalmos with coloboma is one specific type of complex microphthalmos and is caused by an incomplete closure of the embryonic fissure. It also may occur as both a sporadic and hereditary form. It may be associated with a number of systemic diseases, including the coloboma, heart defect, atresia cochonal, retarded growth, genital hypoplasia, ear anomalies (CHARGE) syndrome. Recognition of this entity when evaluating a child with microphthalmos is important, because the heart defects in the CHARGE association can be lethal. Autosomal-dominant colobomatous microphthalmos is a well-known and important disorder. It occurs without an associated systemic abnormality and has variable expressivity and penetrance. Family members of affected patients should receive appropriate genetic counseling.

Microphthalmos with cyst results from the proliferation of neuroectoderm at the edge of a persistent embryonic fissure. The cavity of the cyst is continuous with the interior of the microphthalmic globe. Rudimentary optic nerve fibers can be seen within the cyst wall.²⁷ The microphthalmic eye itself often is overshadowed by the larger orbital cyst (Fig. 53.5).²⁸ Cases of extreme microphthalmos may be confused with anophthalmia. The anterior segment of the microphthalmic eye may appear normal, although it commonly displays marked disorganization and iridocorneal adhesions. The lens is frequently cataractous and dislocated.²⁹ The retina usually is detached, disorganized, and gliotic.³⁰ No consistent association has been documented between microphthalmos with cyst and a specific systemic anomaly. Systemic disorders reported with microphthalmos with cyst include central nervous system (CNS) defects (e.g., meningoencephalocele, hydrocephalus) and cardiac, urogenital, facial, and skeletal abnormalities.³¹

Congenital aphakia, a very rare anomaly, can be divided into two types: primary, in which a lens failed to develop; and secondary, in which a lens developed to some degree, but either was resorbed or extruded through a corneal perforation before or during birth.² Primary congenital aphakia has been characterized histologically by aplasia of the anterior segment. This defect may result from anomalous invagination of the optic vesicle, which disturbs the normal relationship between the optic vesicle and the surface ectoderm. The lack of surface ectodermal induction may lead to widespread anterior and posterior segment anomalies.³⁶ The abnormal optic vesicle invagination also may be accompanied by defects in the closure of the fetal fissure, and therefore by typical colobomas.

Secondary congenital aphakia is more common than is the primary type. The lens is usually represented by a wrinkled capsule. Several attempts have been made to explain secondary aphakia. One theory suggests that the lens may develop normally, but that the capsule is thinner than usual and ruptures. Intrauterine inflammations also may lead to degeneration of the lens and to subsequent capsular shrinkage, which is sometimes accompanied by mesenchymal infiltration of the lens remnant.

Microspherophakia is a bilateral condition in which the lens is usually small and spheric. Following pupillary dilation, the lens edge may be identified with a slit lamp. The small size and spheric shape of the lens may result in significant myopia. The elongated zonules may permit the lens to move forward, increasing the area of iridolenticular contact.³⁷ This mechanism may lead to pupillary block. Miotics may increase the pupillary block, and mydriatics may relieve it, a paradox that Urbanek³⁸ termed inverse glaucoma and that others have confirmed exists.^39,40 Microspherophakia has been reported in association with such systemic entities as Marfan syndrome, homocystinuria, Alport syndrome, Klinefelter syndrome, and Weill-Marchesani syndrome.^41,42,43,44 It may occur as an isolated anomaly transmitted as either an autosomal-dominant or autosomal-recessive condition.⁴⁵ The lens is typically spheric before the fifth or sixth month of fetal life, so an arrest in lenticular development at this stage would explain uncomplicated microspherophakia.

Anterior lenticonus is a rare bilateral condition in which the anterior surface of the lens bulges centrally. It may be accompanied by lens opacities or other eye anomalies and is a prominent feature of Alport syndrome.^46,47 Examination by retinoscopy or by ophthalmoscopy shows a dark area resembling an oil droplet in the center of the lens. The increased curvature of the central area may cause high myopia.

Histologic examination of the anterior capsule in anterior lenticonus shows it to be one-third the normal thickness, having multiple capsular dehiscences containing fibrillar material and vacuoles.^48,49 The capsular fragility observed in this condition is a result of a mutation in the gene that encodes for one or more chains in type IV collagen.^50,51,52 The fragility of the anterior capsule most likely forms the basis for the progressive lenticonus and anterior polar cataract, as well as the susceptibility of the lens capsule to rupture, either spontaneously or after minor trauma.⁵³

Posterior lenticonus, which occurs more commonly than does anterior lenticonus, is an ectasia of the posterocentral surface of the lens. It often is associated with progressive lens opacities of the posterior cortex. The majority of cases are unilateral, and the condition is found more frequently in females than in males. When no lens opacities are present, the clinical appearance of posterior lenticonus resembles the oil droplet appearance of anterior lenticonus. The characteristic localized posterior bulge can be seen with a slit lamp. The etiology of posterior lenticonus is unknown. Because the zonules exert traction on the lens and determine its shape, focal defective zonular traction along the posterior lens capsule may account for abnormal curvature in the area.

Developmental cataracts may be classified according to the location (e.g., nuclear, polar) or configuration (e.g., coralliform, blue dot) of the opacity. Progress has been made in determining the etiology of many congenital cataracts. The various factors that might cause these lens defects include hereditary factors, infectious agents, metabolic abnormalities, toxins, endocrinologic effects, and ionizing radiation. Despite a meticulous medical history and a thorough clinical and laboratory workup, the cause of a congenital cataract in any particular patient can still escape identification. Because they may develop at any time during the life of the fetus, lens opacities often make excellent markers for the timing of developmental defects. In general, developmental aberrations affecting the primary lens fibers may cause central lens opacities. If the secondary fibers are opacified, a clinical opacity restricted to a zone (zonular cataract) may occur.