Fig. 6.1
The development of the anterior segment is characterized by the migration of three successive waves of neural crest cells. I The first wave of neural crest cells migrates between the surface ectoderm and the lens. These cells will differentiate into the corneal endothelium as well as the endothelial cells of the trabecular meshwork. The corneal endothelium will start to lay down Descemet membrane in the eighth week. II The second wave of cells migrates between the primitive corneal epithelium and endothelium, giving rise to keratocytes and the corneal stroma. III The third wave of neural crest cell migration occurs between the primitive corneal endothelium and the lens to form the iris stroma
Table 6.1
Ocular and systemic neural crest derivatives
Ocular and orbital structures | Systemic structures |
|---|---|
Corneal stroma Sclera Corneal endothelium Trabecular meshwork Iris and choroidal stroma Ciliary muscle Melanocytes Sheaths and tendons of extraocular muscles Meningeal sheaths of the optic nerve Schwann cells of ciliary nerves Ciliary ganglion Orbital bones, cartilage and connective tissues Muscular layer and connective tissue sheaths of all ocular and orbital vessels | Teeth (odontoblasts and dental papillae) Dermis, smooth muscle, and adipose tissue of skin of head and neck Melanocytes Cranial nerves III, V, VII, VIII, IX and X Sensory neurons and dorsal root ganglia Sympathetic and parasympathetic ganglia Schwann cells of peripheral nerves Pituitary gland Adrenal medulla Parafollicular cells of thyroid Thymus Salivary and lacrimal glands Craniofacial cartilage and bone Bones of middle ear Tracheal and laryngeal cartilage Semilunar heart valves Cardiac septum Muscular layer and connective tissue sheaths of the large arteries |
The anterior chamber first appears as a potential space between the corneal endothelium and the iris stroma in the eighth week and grows to a slit-like space by the end of the third month of gestation (Barishak 2001). A marked increase in the curvature of the cornea also occurs in the third month, leading to the demarcation of the corneoscleral limbus (Duke-Elder and Cook 1963; Hogan et al. 1971). The diameter of the cornea increases from 4.2 mm in the 16th week of gestation to 9.6 mm at term (Barishak 2001).
Genetics
The development of the anterior segment has several genetic influences. Transcription factors, such as homeobox genes, are particularly important in this process as they act as “master control” genes in embryological development by activating or suppressing the expression of subordinate genes. Defects in homeobox genes have been found in several conditions with either congenital corneal opacity or ASD (Table 6.2).
Table 6.2
Genetics of anterior segment dysgenesis, congenital/neonatal corneal opacity, and anomalies of corneal size and shape
Disease | Gene | Locus |
|---|---|---|
CHEDa | SLC4A11 | 20p13 |
CHSD | DCN | 12q22 |
PPCD PPCD1a PPCD2 PPCD3 | – COL8A2 ZEB1b | 20p11.2-q11.2 1p34.3-p32.3 10p11.2 |
XECD | – | Xq25 |
CYP1B1 cytopathy | CYP1B1 | 2p22.2 |
Iridocorneal adhesions | PITX2b, FOXC1, CYP1B1, PAX6b | – |
Primary aphakia and lens fails to separate from cornea | FOXE3 | 1p33 |
Peters anomaly | CYP1B1 PAX6b PITX2b | 2p22.2 11p13 4q25 |
Peters-plus syndrome | B3GALTL | 13q12.3 |
Aniridia | PAX6b | 11p13 |
Primary congenital glaucoma GLC3A GLC3D | CYP1B1 LTBP2 | 2p22.2 14q24.3 |
Intracorneal cyst | Digenic FOXC1 and PITX2b | 6p25.3/4q25 |
Axenfeld-Rieger syndrome | FOXC1 PITX2b | 6p25.3 4q25 |
Megalocornea | CHRDL1 | Xq23 |
Cornea plana | ||
CNA1 and CNA2 | KERA | 12q21.33 |
Anterior Segment Dysgenesis
ASD is a general term that encompasses several congenital entities including Peters anomaly, sclerocornea, aniridia, and Axenfeld-Rieger syndrome. No genotype–phenotype relationship is implied by this term.
The differential diagnosis of congenital and neonatal corneal opacities has been traditionally taught using the STUMPED (Sclerocornea, Tears in Descemet membrane, Ulcers, Metabolic diseases, Peters anomaly, Endothelial dystrophies, Dermoids) acronym. Recently, a different classification system has been suggested to improve the consistency of the terminology used in the literature, facilitate the establishment of phenotype–genotype correlations, and optimize the management of patients with neonatal corneal opacity (Nischal 2007, 2012). Both classification systems are compared in Table 6.3.
Table 6.3
Traditional and novel classification of congenital and neonatal corneal opacities
Traditional (STUMPED) | Novel classification |
|---|---|
Sclerocornea | Primary corneal disease |
Tears in Descemet membrane Congenital (infantile) glaucoma Forceps injury and other trauma | Corneal dystrophies Congenital hereditary endothelial Dystrophy Posterior polymorphous corneal Dystrophy Congenital hereditary stromal Dystrophy X-linked endothelial corneal Dystrophy Corneal dermoid Peripheral sclerocornea CYP1B1 cytopathy |
Ulcers Viral Bacterial Fungal Neurotrophic | |
Metabolic diseases Mucopolysaccharidoses Mucolipidoses | |
Peters anomaly | Secondary corneal disease |
Endothelial dystrophies Congenital hereditary endothelial Dystrophy Posterior polymorphous dystrophy | Congenital Kerato-irido-lenticular dysgenesis Iridocorneal adhesions Lens fails to separate from cornea Lens separates but fails to form Thereafter Lens separates and forms, but there is Late corneal apposition Lens fails to form Irido-trabecular dysgenesis Primary congenital glaucoma. Intracorneal cyst Axenfeld-Rieger syndrome Congenital aniridia Acquired Infection Viral Bacterial Trauma Forceps injury Amniocentesis injury Metabolic Mucolipidosis IV |
Dermoids |
The traditional classification is wrought with confusing inaccuracies. For example, the term sclerocornea is often used to designate total opacification of the cornea. However, this term should be reserved for cases of scleralization of the peripheral cornea. Conversely, the term Peters anomaly is used as a waste basket for different forms of central corneal opacification (Mataftsi et al. 2011). A more specific classification scheme is necessary to improve our understanding and management of these conditions.
Congenital and neonatal corneal opacification can result from either primary or secondary corneal disease. Primary causes include developmental anomalies that are present at birth in which the primary defect localizes to the cornea. Secondary causes of corneal opacification include the more complex kerato-irido-lenticular and irido-trabecular dysgeneses, as well as anomalies acquired from readily identifiable insults such as infection or trauma.
Primary Corneal Opacification
Causes of primary corneal opacification include the corneal dystrophies, dermoids, peripheral (isolated) sclerocornea, and CYP1B1 cytopathy.
Corneal Dystrophies
Congenital hereditary endothelial dystrophy (CHED), congenital hereditary stromal dystrophy (CHSD), posterior polymorphous corneal dystrophy (PPCD), and X-linked endothelial corneal dystrophy (XECD) are the four corneal dystrophies present in infancy.
CHED
CHED is characterized by bilateral, symmetric, and diffuse corneal edema due to a primary dysfunction of the corneal endothelium. Histopathological examination of excised corneal buttons shows an abnormal, degenerated corneal endothelium, thickening of the posterior non-banded layer of Descemet membrane as well as stromal and epithelial edema (Kirkness et al. 1987; Ehlers et al. 1998). CHED was previously thought to occur with both autosomal-dominant (CHED1) and autosomal-recessive (CHED2) patterns of inheritance. However, a review of CHED1 pedigrees led to the reclassification of this disease within the PPCD spectrum, leaving only the autosomal-recessive form of CHED (Aldave et al. 2013a, b; Weiss et al. 2015). Thus, CHED is characterized by dense but non-progressive corneal edema present at birth. Photophobia and epiphora are absent. These patients develop nystagmus due to early opacification of the visual axis (Judisch and Maumenee 1978). Mutations in the SLC4A11 gene, which codes for a sodium-borate cotransporter, have been identified in several lineages with CHED (Vithana et al. 2006; Jiao and Sultana 2007). The incidence of CHED appears to be higher in families of Middle Eastern descent (Al-Rajhi and Wagoner 1997).
As an isolated disease of the corneal endothelium, CHED is believed to have a relatively good prognosis following corneal transplantation. However, when using the new classification and isolating congenital cases of CHED, the prognosis appears more guarded, with a graft survival rate of 56% (Al-Rajhi and Wagoner 1997).
Descemet stripping-automated endothelial keratoplasty (DSAEK) shows promise in the surgical management of CHED. Stripping of the endothelium and Descemet membrane appears to be optional as it does not offer a significant advantage in graft adherence or postoperative visual acuity when compared to non-stripping procedures (Ashar et al. 2013a). Endothelial keratoplasty allows for earlier visual rehabilitation when compared to full-thickness transplantation, but challenges such as poor visualization due to dense opacity, management of the phakic lens, and postoperative positioning need to be considered on an individual basis (Ashar et al. 2013b).
CHSD
CHSD is an extremely rare dystrophy characterized by limbus-to-limbus corneal clouding. Ill-defined, flake-like opacities are found throughout the corneal stroma, but appear to be most dense anteriorly. The opacities are present at, or shortly, after birth, and accumulate over years. Corneal thickness may be normal or increased (Bedrup et al. 2005; Pouliquen et al. 1979). Most patients require corneal transplantation by early adulthood. Excellent visual outcomes are achievable following penetrating keratoplasty, but opacities may recur in the graft (Bedrup et al. 2005). CHSD has been linked to mutations in the decorin (DCN) gene which leads to truncated decorin protein aggregation and accumulation between collagen lamellae (Bedrup et al. 2010).
PPCD
Bilateral polymorphous changes of the posterior cornea are the distinctive finding in PPCD. Slit lamp examination reveals grouped vesicles, geographic lesions, and broad bands with scalloped edges. Such alterations can be visualized with specular and confocal microscopy (Cibis et al. 1977). Stromal edema, corectopia, and iridocorneal adhesion may also be observed. Glaucoma, which can present with either an open- or a closed-angle pathophysiology, is common.
The corneal endothelium in PPCD shows epithelial characteristics on histopathologic exam. The endothelium is multilayered; and microvilli, cytokeratin, and intercellular desmosomes are present. Descemet membrane is diffusely thickened and multilaminated (Moroi et al. 2003; Krachmer 1985). Because of their ability to proliferate, the abnormal endothelial cells can migrate to cover the trabecular meshwork, leading to impaired aqueous humor outflow.
PPCD is an autosomal-dominant corneal dystrophy. Mutations at three loci have been identified (Table 6.2) (Gwilliam et al. 2005; Biswas et al. 2001; Krafchak et al. 2005). While the locus for PPCD1 is known, the causative gene remains to be identified. The gene for PPCD2 codes for the alpha 2 chain of collagen type VIII (COL8A2). PPCD3 is caused by mutations in the zinc-finger E-box binding homeobox 1 gene (ZEB1), which is also known as transcription factor 8 (TCF8). Irregular astigmatism and excessive corneal steepening have been associated with PPCD3 (Aldave et al. 2013a, b).
Corneal transplantation is required in only a minority of patients and typically not until adulthood. Both penetrating keratoplasty and DSAEK have been reported to give good outcomes (Sella et al. 2013). However, the disease may recur in the graft with migration of host endothelium onto the donor (Sekundo et al. 1994). Graft survival may also be limited by the presence of glaucoma, especially when iridocorneal adhesions are present (Krachmer 1985).
XECD
XECD is a recently reported corneal dystrophy (Schmid et al. 2006). In the most severe cases, patients present at birth with significant bilateral corneal clouding with a ground glass or milky appearance. Milder cases are found to have endothelial lesions resembling moon craters and subepithelial band keratopathy. Asymptomatic carriers of the disease trait also demonstrate these moon crater-like lesions of the posterior cornea. Histopathologic examination reveals irregular thickening and small excavations in Descemet membrane. The endothelial cells have an atypical distribution with multilayering in some areas, while other areas are left bare. The corneal epithelium and Bowman layer appear thinned and the anterior corneal stroma shows disorganization of collagen lamellae. The prognosis following penetrating keratoplasty is good, with no disease recurrence reported to date (Schmid et al. 2006).
Epibulbar Choristomas (Dermoids)
Epibulbar choristomas, congenital tumors consisting of normal tissue in an ectopic location, have an incidence of approximately 1 in 10,000. Dermoids are choristomas consisting of skin and dermal appendages only while complex choristomas contain additional tissue types such as cartilage, bone, and lacrimal gland.
Most cases of epibulbar choristomas occur as an isolated ocular finding. However, in one-third of cases, they occur as part of several syndromes such as Goldenhar syndrome and epidermal nevus syndrome (Mansour et al. 1989). Epibulbar choristomas are most often found at the inferotemporal limbus. However, they can also involve the central cornea. These lesions tend to be oval or round and yellowish white. A lipid arcus may be seen in the adjacent cornea and fine hairs may grow at the surface of the lesion. Elevated choristomas can cause corneal dellen formation and ocular irritation. By causing flattening of the adjacent cornea and astigmatism, limbal lesions may lead to anisometropic amblyopia. Choristomas are generally stationary, although some enlargement may be seen at the time of puberty (Trubnik et al. 2011).
The indications for surgical intervention include significant astigmatism, amblyopia, corneal irritation, and poor cosmesis. While surgical removal of the lesion may not lead to significant change in corneal astigmatism, the resulting normalized ocular surface contour allows for fitting with a rigid contact lens (Scott and Tan 2001). The elevated portion of the lesion may be removed by simple excision, shave dissection, or superficial keratectomy. These procedures leave a scar in the underlying cornea and, in some cases, an unsightly pseudopterygium may occur postoperatively. Lamellar keratoplasty using a fresh or gamma-irradiated corneoscleral donor graft often leads to better cosmetic results (Panda et al. 2002). Alternatively, multilayered amniotic membrane and fibrin tissue glue can be used to fill the resulting defect (Pirouzian et al. 2011). However, excision procedures carry a risk of corneal perforation as some choristomas may extend deeply into the stroma (Watts et al. 2002). To mitigate this risk, ultrasound biomicroscopy (UBM) can be performed to assess lesion depth preoperatively. Corneal tissue should also be available during surgery. Gamma-irradiated corneal tissue is particularly well suited for this purpose because of its long shelf life at room temperature. Penetrating keratoplasty is indicated when the dermoid involves the visual axis.
Peripheral Sclerocornea
Sclerocornea refers to peripheral whitening of the cornea that may extend toward the visual axis. As mentioned previously, the term sclerocornea should never be applied to total corneal opacification. Sclerocornea is congenital and non-progressive. It occurs bilaterally in 90% of cases. With loss of a clearly demarcated limbus, normal vessels from the sclera, episclera, and conjunctiva cross onto the area of scleralization. As the normal sclera has a flatter curvature than the cornea, 80% of eyes with sclerocornea will also have cornea plana. Dysgenesis of the anterior chamber angle with consequent glaucoma is common. Less commonly associated ocular malformations include microphthalmos, iridocorneal adhesions, persistent pupillary membranes, coloboma, iris dysgenesis, posterior embryotoxon, cataract, nystagmus, and esotropia (Kenyon 1975; Elliott et al. 1985; Harissi-Dagher and Colby 2008).
The histopathology of sclerocornea reveals features typical of scleral tissue. Contrary to the uniform, parallel, and organized lamellar structure of corneal collagen, scleral collagen shows fibers of variable diameter, which are arranged in an irregular, non-lamellar fashion. The underlying Descemet membrane and endothelium may be attenuated or absent (Kanai et al. 1971).
Half of the cases of sclerocornea are sporadic. For others, both autosomal-recessive and autosomal-dominant patterns of inheritance have been reported. The autosomal-recessive form is classically described as being more severe. However, many of the previously reported severe autosomal-recessive cases manifested total corneal opacification and should not have been designated as sclerocornea. Similarly, many systemic findings and syndromes have been associated with ‘sclerocornea’, but rather referred to total corneal opacification (Elliott et al. 1985). MIDAS syndrome (microphthalmia, dermal aplasia and sclerocornea), which is also known as MLS syndrome (microphthalmia with linear skin defects), or the Xp22.3 microdeletion syndrome, is one important example of a syndrome presenting with peripheral sclerocornea (Cape et al. 2004). These patients require a systemic work-up searching for concomitant congenital heart defects, hypospadias, and neurodevelopmental anomalies.
Most cases of sclerocornea will only require careful refraction and amblyopia management. Corneal transplantation is considered for opacities impeding on the visual axis. Unfortunately, penetrating keratoplasty has a poor surgical outcome in sclerocornea when compared to other causes of congenital corneal opacification. Graft failure occurs in 75% of cases and the average time to failure is 36 months (Kim et al. 2013). These poor outcomes are explained by the presence of peripheral vascularization as well as the small corneal diameter seen in sclerocornea.
CYP1B1 Cytopathy
Mutations in the CYP1B1 gene are known to cause primary congenital glaucoma (GLC3A). CYP1B1 mutations have also been reported in rare cases of congenital corneal opacification with iridocorneal and/or keratolenticular adhesion as well as posterior embryotoxon and iris hypoplasia (Vincent et al. 2001; Edward et al. 2004; Chavarria-Soley et al. 2006; Kelberman et al. 2011). The corneal phenotype of CYP1B1 cytopathy resembles the original description of the von Hippel internal ulcer. Clinical exam shows diffuse, limbus-to-limbus corneal opacity and absent iridocorneal and kerato-irido-lenticular adhesions. On histopathology, loss of central Bowman layer, Descemet membrane, and endothelium as well as infiltration by stromal cells is seen. Corneal transplantation has a good survival rate in these cases, but the visual prognosis is guarded due to progressive glaucoma (Kelberman et al. 2011).
Secondary Corneal Opacification
Secondary corneal opacification may be congenital or develop later in the neonatal period.
Congenital
The congenital causes of secondary corneal opacification include kerato-irido-lenticular and irido-trabecular dysgenesis. UBM evaluation is helpful to delineate the extent of iridocorneal adhesions and the degree of differentiation of the crystalline lens. For familiarity, the traditional Peters anomaly is discussed along the different forms of kerato-irido-lenticular dysgenesis (KILD).
Kerato-Irido-Lenticular Dysgenesis (KILD) Versus Peters Anomaly
In the traditional nomenclature, Peters anomaly is defined by the presence of a central leukoma with a defect in the underlying posterior cornea plus iridocorneal adhesions. The peripheral cornea is typically clear. On histology, the central posterior corneal stroma, descemet membrane, and endothelium are absent in the area of opacification. Iris strands extend from the iris collarette onto the cornea, more or less delineating the area of opacity. The phenotype is subclassified into two types. Peters anomaly type 1 occurs in cases with a central leukoma and iridocorneal adhesions but a normal lens. Peters anomaly type 2 is characterized by keratolenticular adhesions. The lens is almost invariably cataractous. Peters anomaly is bilateral in 80% of cases but may be asymmetric (Waring et al. 1975; Kenyon 1975; Reese and Ellsworth 1966).
Glaucoma occurs in 50–70% of patients with Peters anomaly due to dysgenesis of the trabecular meshwork and Schlemm canal (Yang et al. 2004). Cataract or keratolenticular adhesions are additional risk factors for the development of glaucoma. The glaucoma associated with Peters anomaly is often severe and difficult to control despite aggressive medical and surgical intervention (Yang et al. 2004).
Other ocular findings that may accompany Peters anomaly include microphthalmos, microcornea, cornea plana, sclerocornea, uveal coloboma, ptosis, as well as optic nerve and foveal hypoplasia.
Peters anomaly is typically an isolated ocular defect. Systemic findings are seen in the Peters-plus syndrome, a separate autosomal-recessive disease also known as the Krause–Kivlin syndrome (van Schooneveld et al. 1984; Kivlin et al. 1986). These include short stature, short limbs, abnormal ears, thin upper lip, cleft lip, and palate and mental retardation. Other reported systemic associations include congenital central nervous system, hearing, cardiac, genitourinary, and spinal defects (Traboulsi and Maumenee 1992).
The management of Peters anomaly should involve a careful medical work-up with attention to the organ systems listed above, amblyopia management, as well as control of IOP. Surgical intervention to clear the visual axis should be guided by the overall potential for functional vision. Some milder cases of corneal opacification may spontaneously regress over time. In the presence of a small corneal leukoma and no cataract, an optical iridectomy has satisfactory outcomes while being the least invasive approach (Zaidman et al. 1998). Corneal transplantation may be considered in selected cases, but graft survival rates depend highly on the underlying phenotype (Yang et al. 2009). Implantation of a Boston keratoprosthesis can be considered as an alternative, as it quickly establishes a clear visual axis and facilitates the refractive component of amblyopia management (Aquavella et al. 2007). However, long-term outcomes of keratoprosthesis surgery in children have not been published to date and the potential for blinding complications should not be underestimated.
A more accurate assessment of the surgical risk–benefit ratio for secondary corneal opacification may be achieved using the classification proposed by Nischal (2012). This new terminology sub-classifies KILD into five entities.
- 1.
Iridocorneal adhesions describe what was traditionally referred to as Peters anomaly type 1. This malformation causes an avascular leukoma that may involve the center, periphery, or entire area of the cornea. Because the lesion is avascular, these eyes tend to do well following keratoplasty. In one series, 54% of children in this category achieved a visual acuity of 20/100 or better after keratoplasty (Zaidman et al. 2007). Mutations in PITX2, FOXC1, CYP1B1, and PAX6 have been associated with iridocorneal adhesions (Nischal 2012).
- 2.
If the lens fails to separate from cornea, a vascularized corneal opacity occupies either the central or the entire cornea (Peters anomaly type II using the traditional nomenclature). The lens remains adherent to the cornea following failure of the lens vesicle to separate from the surface ectoderm. The anterior lens capsule appears to be absent in the area of adhesion and the lens itself is often cataractous. The prognosis for corneal transplantation is limited by the necessary concomitant removal of the lens, leaving the patient aphakic and at high risk of anterior vitreous prolapse. Penetrating keratoplasty has a much more guarded prognosis with a success rate of only 14% (Bhandari et al. 2011). Heterozygous mutations in FOXE3 have been reported to cause this entity (Iseri et al. 2009; Semina et al. 2001).
- 3.
When the lens separates but fails to form thereafter, the cornea is completely opaque and vascularized. Only a small lens remnant is visible on UBM. The prognosis for corneal transplantation is poor.
- 4.
If the lens separates and forms, but there is late corneal apposition, corneal opacification is generally central and avascular. As evidence of prior lens separation from the cornea, the anterior lens capsule is intact and can be seen on UBM. The pathophysiology may involve hypoxia, retrolental membranes that contract and push the lens anteriorly as seen in persistent fetal vasculature or vitreoretinal dysplasias or lens–cornea touch from a very shallow anterior chamber as is seen in aniridia (Nischal 2012). Lens extraction alone may allow the cornea to clear, rendering corneal transplantation unnecessary. To avoid further damage to the endothelium, the anterior lens capsule should not be peeled from the posterior cornea.
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