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Invited Keynote Address

Genetics of Congenital Corneal Opacification—Impact on Diagnosis and Treatment

Nischal, Ken K. MD, FRCOphth

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doi: 10.1097/ICO.0000000000000552
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Abstract

Imagine 4 tribes communicating using a language the words of which have a different meaning for each tribe. Now imagine that the 4 tribes' intercommunications have an effect on the well-being of a fifth tribe. The intuitive reaction would be for all 4 tribes to get together and clarify the language they use regardless of habit or convenience. The language alluded to is the nomenclature used to describe congenital corneal opacity (CCO) and neonatal corneal opacity (NCO); the 4 tribes are pediatric ophthalmologists, corneal surgeons, comprehensive ophthalmologists, and geneticists. The fifth tribe is the children and families affected by CCO or NCO.

WHAT IS THE EVIDENCE THAT SUCH A PROBLEM EXISTS?

The traditional way of describing CCO or NCO is to use the pnemonic “STUMPED,” where “S” is for sclerocornea, “T” is for trauma, “U” is for ulcer, “M” is for metabolic disorders, “P” is for Peters anomaly, “E” is for endothelial dystrophy, and “D” is for dermoid. It is noteworthy that 3 of these entities are signs and not a diagnosis. For instance, trauma is a diagnosis of the cause of the opacity, as is metabolic disorders, endothelial dystrophy, and dermoid. The rest, ulcer, sclerocornea, and Peters anomaly, are only signs without an etiology. It seems odd to have a way of remembering the causes of CCO or NCO and have 3 of the 7 terms be only signs. This lays the ground for confusion.

In a report on the clinicopathological correlation of CCO using high-frequency ultrasound, we showed that 40% of the clinical phenotype was wrong when evaluated by high-frequency ultrasound, and we further showed that where histology was available, the high-frequency ultrasound diagnosis was confirmed.1

This led to the conclusion that 2 in 5 diagnoses made without the aid of high-frequency ultrasound were likely incorrect. Moreover, this work revealed that the total corneal opacification often alluded to as sclerocornea often had high-frequency ultrasound characteristics of Peters anomaly.

Literature searches at around the same time revealed a plethora of genotype–phenotype correlations where using only a clinical evaluation without anterior segment imaging revealed contradictory genotyping for Peters anomaly.2–5 If one considers that Peters anomaly is a sign and only a sign, this is not a surprise: it is akin to performing genotype studies in cases of a cough!

As recently as 2014, whole exome sequencing was performed on 27 patients with Peters anomaly, but there were no phenotypic descriptions or images or anterior segment imaging.6 This is confusing and somewhat perturbing to clinician scientists.

In a recent review of chromosomal abnormalities causing congenital corneal opacification,7 the authors found that of the 28 articles in which the term “sclerocornea” was used, it described cornea plana/peripheral scleralization in 13 articles, whereas in the remaining 15, it signified total corneal opacification regardless of etiology. Similarly, in 4 of 17 articles, in which the term “Peters anomaly” was used, it described a complete corneal opacity, without sonographic or histologic evidence of iridocorneal or keratolenticular adhesions. Ocular ultrasonography was used to better describe the phenotype in only 4 articles and ultrasound biomicroscopy (UBM) in only 1 article.7

Another point of possible confusion is that in the world of genetics, the term “anterior segment mesodermal dysgenesis” refers to a specific autosomal dominant condition in which cataract, corneal opacity, and glaucoma can coexist and is due to mutations in PITX3.8 Ophthalmologists refer to developmental anomalies of the anterior segment as anterior segment dysgenesis. These 2 terms are close enough to the ear, and need clarification when used.

The purpose of this discussion is to develop a universally accepted language, which will help investigate and develop better phenotyping for better management of congenital and neonatal corneal opacities that affect visual development.

PROPOSED CLASSIFICATION

NCO or CCO may be considered as being caused by primary corneal disease (Fig. 1) or secondary corneal disease (Fig. 2). Primary corneal disease is all developmental and may be isolated to the cornea or have a related systemic component. Secondary corneal disease may be developmental or acquired.

FIGURE 1
FIGURE 1:
Scheme showing CCO/NCO classification as pertains to primary corneal disease. Those conditions in green have been shown to do relatively well after keratoplasty. PPMD, posterior polymorphous corneal dystrophy; X-L ECD, X-linked endothelial corneal dystrophy; CHSD, congenital hereditary stromal dystrophy; CNA, cornea plana.
FIGURE 2
FIGURE 2:
Scheme showing CCO/NCO classification as pertains to secondary corneal disease. Those conditions in green do relatively well with keratoplasty but those in red do relatively poorly. PFV, persistent fetal vasculature; AR, Axenfeld–Rieger.

Primary Corneal Disease

At present, there are 4 types of primary corneal disease that cause CCO or NCO.

  1. Corneal endothelial dystrophy
  2. Corneal dermoid
  3. Cornea plana (peripheral sclerocornea)
  4. CYP1B1 cytopathy (Von Hippel ulcer).

Corneal Endothelial Dystrophy

This include congenital hereditary endothelial dystrophy (CHED), posterior polymorphous corneal dystrophy (PPCD), X-linked endothelial corneal dystrophy, and congenital hereditary stromal dystrophy.

Congenital Hereditary Endothelial Dystrophy

The so-called autosomal dominant inherited CHED (formerly CHED1) is insufficiently distinct to continue to be considered a unique corneal dystrophy.9 On review of almost all the published cases, the description appeared most similar to a type of PPCD linked to the same chromosome 20 locus (PPCD1). Therefore, all cases of CHED are likely to be due to autosomal recessive inheritance and should be screened for hearing loss (Harboyan syndrome).10 The gene implicated for CHED2 is SLC4A11.11 CHED is characterized by diffuse corneal edema and thickening of Descemet membrane affecting both eyes usually symmetrically presenting at birth.6 The corneal edema can vary from a blue-gray ground-glass appearance to total corneal opacification. Corneal clouding is present at birth or within the neonatal period.

Histological features of CHED include diffuse epithelial and stromal edema, defects in the Bowman membrane, paucity of endothelial cells and multinucleated cells, and a thickened Descemet membrane reflecting abnormal secretion by the endothelial cells.12

Reports of CHED with glaucoma are published,13 but caution is also raised about the possibility of artifactually raised pressure readings due to the very thick corneas seen in these cases.14 Ancillary signs of congenital glaucoma must be looked for to make the correct diagnosis (eg, increased horizontal corneal diameter, Haab striae, and buphthalmos).

Because CHED is a primary corneal disease, it is not surprising that most studies of penetrating keratoplasty (PKP) in the literature report relatively good graft survival and outcomes, although amblyopia due to marked early visual deprivation remains a problem.15,16 More recently, reports of Descemet stripping automated endothelial keratoplasty and Descemet stripping endothelial keratoplasty have been published, and the early reports are promising in terms of the graft survival outcome and visual rehabilitation.17

Posterior Polymorphous Corneal Dystrophy

Posterior polymorphous corneal dystrophy rarely presents at birth1,9 when congenital glaucoma is often the differential diagnosis, but a normal corneal diameter for age and the absence of buphthalmos and Haab striae help steer the clinician to the diagnosis of corneal endothelial dystrophy. The family history or positive examination identifying an affected parent is also helpful. Locus heterogeneity has been shown for PPCD, with mapping confirmed to chromosome 20 (the PPCD1 locus), associated with mutations in collagen, type VIII, alpha 2 gene (COL8A2), on chromosome 1 (the PPCD2 locus), and associated with mutations in the zinc finger E-box binding homeobox 1 gene (ZEB1) on chromosome 10 (the PPCD3 locus).11 Although strong evidence exists endorsing the involvement of a gene in the PPCD1 locus and ZEB1 in the pathogenesis of PPCD, the same is not true for COL8A2 in the pathogenesis of PPCD.11

There are no case series limited to congenital PPCD, but it is the author's experience and that of the pediatric case series published1 that being a primary corneal disease, the outcomes of PKP are reasonably good even in children and infants.

X-Linked Endothelial Corneal Dystrophy

X-linked endothelial corneal dystrophy is a very rare condition with only a single several generation Austrian family having been reported.18 In the only infant affected, corneal transplant was not necessary, but it was thought that with time the endothelial dystrophy worsened necessitating intervention (Fig. 3). Again, the report suggests a good outcome of PKP in an adult.

FIGURE 3
FIGURE 3:
A child having X-linked endothelial corneal dystrophy. Note the variable corneal haze and the posterior or deep stromal edema on UBM with defects seen in the endothelial–Descemet membrane complex.
Congenital Hereditary Stromal Dystrophy

Mutations in the decorin (DCN) gene at 12q22 have been implicated for congenital hereditary stromal dystrophy, also known as congenital stromal corneal dystrophy. There is diffuse limbus-to-limbus clouding, with flake-like opacities in the stroma without vascularization or staining of the cornea.9 Good surgical outcomes have been reported in cases in which deep anterior lamellar keratoplasty has been performed.10

Corneal Dermoid

Corneal dermoids are choristomas, which are usually epibulbar and may be isolated or more commonly associated with Goldenhar syndrome. They may also be central corneal and obstruct the visual axis. Large central corneal dermoids may be fleshy and elevated or flat and reticular.19 The latter should initiate a search for trisomy 8 mosaicism including a retest with greater numbers of cells counted to look for mosaicism. Diagnosis of trisomy 8 mosaicism is important because this condition may be associated with other systemic abnormalities that may not be obvious, for example, cardiac issues.

If there is an ipsilateral area of the alopecia/nevus of the scalp, a diagnosis of encephalocraniocutaneous lipomatosis (Fig. 4) should be considered with magnetic resonance imaging being arranged, given the high incidence of intracranial anomalies in this condition.20

FIGURE 4
FIGURE 4:
A child having encephalocraniocutaneous lipomatosis with classic ipsilateral alopecia (star) and the corneal dermoids (white arrow) and lipodermoids (black arrow) (courtesy of Dr A. Molinari).

A particularly unique sign is that of a type of a keloid or hypertrophied keratinized corneal lesion most often seen bilaterally (Fig. 5) in MIDAS or MLS syndrome.21,22 The acronym MIDAS stands for MIcrophthalmia, Dermal Aplasia and Sclerocornea, whereas MLS stands for microphthalmia with linear skin defects. The mere fact that the term sclerocornea is used within this syndrome suggests that the terminology should no longer be used since the authors of one report describe the eye of a case as having “Peters anomaly and sclerocornea.”21

FIGURE 5
FIGURE 5:
A child having microphthalmia with linear skin defects syndrome. Note the unusual appearance of the corneal lesions with keratinization. These lesions have been termed sclerocornea (this syndrome is also known as MIcrophthalmia, Dermal, Aplasia, Sclerocornea—MIDAS), which is misleading. The anterior segment is relatively undisrupted, but there is glaucoma (courtesy of Dr I. Wong).

Lamellar keratoplasty is well described for even large corneal dermoids encroaching the visual axis, with good outcomes.23 For more extensive lesions with secondary iris changes or lens changes, or both, PKP has also been described.24 Outcomes of lamellar keratoplasty are reasonably good, although postoperative astigmatism can still lead to amblyopic visual loss.

Cornea Plana (Peripheral Sclerocornea)

The term sclerocornea (as shown in the discussion above) has been the most misused nomenclature. In a recent review of chromosomal abnormalities causing congenital corneal opacification,7 the authors found that of 28 articles in which the term sclerocornea was used, it described cornea plana/peripheral scleralization in 13 articles, whereas in the remaining 15 articles, it signified total corneal opacification regardless of etiology. Furthermore, in the first article to describe hereditary sclerocornea in 1985,25 the authors described autosomal dominant peripheral sclerocornea with cornea plana.

CNA (cornea plana) has 2 forms: CNA 1 and CNA 2. CNA 1 is clinically characterized by reduced corneal curvature leading in most cases to hyperopia, peripheral sclerocornea, and arcus lipoides at an early age. No gene has been implicated in this condition.26 This is not so for CNA 2, which is autosomal recessive, and mutations in the KERA gene27 encoding the keratocan protein have been described. In this condition, there is again reduced corneal curvature, peripheral sclerocornea, arcus lipoides, and variable central corneal haze with or without iridocorneal adhesions (Fig. 7). Treatment therefore consists of dealing with the refractive error and managing secondary angle closure glaucoma that presents by the second decade of life.

FIGURE 7
FIGURE 7:
Cornea plana with some peripheral scleralization. The cornea is flat, and there is microcornea secondary to the peripheral scleralization.

CYP1B1 Cytopathy

In CYP1B1 cytopathy, glaucoma is present, but the corneal opacity is not due to stromal edema but due to the absence of Descemet and endothelium and the Bowman layer only centrally.3 In theses cases, there are no Haab striae, and the corneal diameter is usually no greater than 11.5 mm. The corneal graft remains clear, but the glaucoma can be very difficult to treat.

These are the cases in which glaucoma is controlled, but the opacity remains and grafting fails to show the features expected for CHED. In such cases, the reader is urged to test for CYP1B128 and review the histology. If this is confirmed, then aggressive antiglaucoma management is highly recommended.

Secondary Corneal Disease

Secondary corneal disease may be the result of developmental anomalies of the anterior segment or of acquired conditions. Causes that are developmental and affect the anterior segment should be considered as those affecting the cornea–iris–lens axis (kerato-irido-lenticular dysgenesis) or those affecting the iris–angle axis (iridotrabecular dysgenesis).

Developmental causes of the anterior segment.

  1. Kerato-irido-lenticular dysgenesis (KILD)
    • a. Iridocorneal adhesions
    • b. Lens fails to separate
    • c. Lens separates but then becomes reapposed
    • d. Lens separates but then fails to continue to form
    • e. Lens fails to form at all
  2. Iridotrabecular dysgenesis
    • a. Primary congenital glaucoma
    • b. Axenfeld–Rieger anomaly (ARA)/syndrome
    • c. Aniridia.

Developmental Causes of the Anterior Segment

KILD: Iridocorneal Adhesions

The opacity here may be central (Fig. 8b), eccentric (Fig. 8a), or less commonly, total. This has traditionally been called Peters anomaly type 1, but by doing so it suggests that it is a disease and not a sign. The most important clinical feature for purely iridocorneal adhesions is that the opacity is invariably avascular. Zaidmann et al29 has shown that results of PKP are good, and a recent review of the literature supports this finding.30 Why iridocorneal adhesions should occur is unknown, but they have been seen with mutations in PITX2, FOXC1, CYP1B1, PAX6, and other genes.2–5 More importantly, iridocorneal adhesions can be seen in one eye (Peters type 1) and keratolenticular adhesions in the other eye (Peters type 2) of the same patient with a known molecular diagnosis (Fig. 9).

FIGURE 8
FIGURE 8:
A, An eccentric corneal opacity due to iridocorneal adhesions; note that the opacity is avascular. B, A central opacity due to iridocorneal adhesions; again note that the opacity is avascular.
FIGURE 9
FIGURE 9:
A child with Peters plus syndrome, which is due to mutations in the B3GALTL gene. The right eye (A) shows a dense central opacity (white arrow) with vascularization (black arrow). The UBM shows keratolenticular adhesions with a cataractous lens (white arrow), which correlates with dense white opacity. In the left eye (B), the opacity is avascular, there is iridocorneal adhesion laterally and posterior excavation centrally (white chevron), which correlates to a ring of relative clearing. This image shows that even when the molecular diagnosis is known, the phenotype may be either iridocorneal adhesion or keratolenticular adhesion, suggesting again that the anterior segment developmental anomalies previously known as Peters anomaly, types 1 and 2, are better termed part of a spectrum within KILD.

KILD: Lens Fails to Separate

Here, there is usually a vascularized central or total corneal opacity presumed to be due to a developmental failure of separation of the invaginating lens vesicle from the overlying surface ectoderm. This is traditionally called Peters anomaly type 2. UBM often shows a cataractous lens with the anterior lens capsule not discernible at the point of attachment (Fig. 9). In a mouse model,30 homozygous mutations in the gene FOXE3 result in developmental failure of lens vesicle–ectoderm separation. Heterozygous mutations in FOXE3 in humans have been described causing a variable phenotype including Peters anomaly.31 Not all cases of failed lens–ectoderm separation are due to FOXE3 mutations, but it is apparent that a primary lens problem can lead to extra-lenticular changes including corneal opacification and glaucoma.

KILD: Lens Separates but Then Becomes Reapposed

The clue to this NOT being a failure of separation is a UBM finding of an intact anterior capsule reflectivity. Surgical removal of the lens is the most effective treatment here, allowing recovery of the endothelium rather than primary corneal transplantation. Note that removal of the lens without peeling off the anterior capsule that is adherent to the cornea often leads to maximal clearance of the corneal opacity. Causes may include the following:

  1. Hypoxia—why exactly this should happen is unclear, but it has been reported32 and also seen by the author.
  2. Persistent fetal vasculature—occurs most likely due to retrolenticular membrane pushing the lens forward to the cornea. It may be seen also in vitreoretinal dysplasias.33
  3. Aniridia—this may be entirely due to a very shallow anterior chamber and the slightest keratolenticular touch or true attachement34,35 (Fig. 10).
  4. FIGURE 10
    FIGURE 10:
    A case of PAX6 confirmed aniridia with keratolenticular adhesion causing central corneal opacity. Treatment in this case was to remove the cataractous lens, which was apposed to the cornea and causing opacity. An intraocular implant was placed and steadied with posterior capsule optic capture.35
  5. Coloboma—usually atypical, which has been recently described.35

KILD: Lens Separates but Fails to Form Thereafter

There is usually total corneal opacification with vascularization, and this can only be diagnosed by UBM or anterior segment ocular coherence tomography (Fig. 11). Because there is only ever a lens remnant present, at best, concomitant vitrectomy is needed at the time of corneal transplantation, which lowers the success rate of transplant surgery.

FIGURE 11
FIGURE 11:
A case of total corneal opacity secondary to the lens having separated but then having failed to form thereafter. Calling this sclerocornea is misleading as the problem is the failure of the lens to develop and not anything that happened within the cornea (Fig. 6).
FIGURE 6
FIGURE 6:
All these various phenotypes have been termed sclerocornea by different observers and authors. It is clear that the term sclerocornea is redundant and misused. This author advocates its abandonment as a description of anterior segment developmental anomalies.

This is distinct from the membranous-type cataracts that are seen in Hallermann–Streiff syndrome. The resorption of the cataracts in such conditions must occur after the cornea has fully formed and is no longer dependent on soluble factors released by the lens to allow appropriate development of the cornea.

KILD: Lens Fails to Form

Also known as primary or congenital aphakia, this rare condition can be recognized by a silver/gray cornea that will still allow transillumination of light. The eyes may be microphthalmic (Fig. 12). This condition has been shown to be due to homozygous or compound heterozygous mutations in FOXE3.31,36 The appearance of the cornea may be explained by the fact that removal of the chick embryo lens results in an opaque thin cornea, presumably because factors are released by the developing lens that promote normal corneal growth.37 Outcomes of PKP for this condition are very poor, most often due to the formation of thick cyclitic membranes resulting in phthisis bulbi. Unfortunately, these cases often develop glaucoma, and the natural history is that when untreated, they will often spontaneously rupture.38 This author tried to place an Ahmed tube in these eyes in the hope of controlling the intraocular pressure.

FIGURE 12
FIGURE 12:
A case of primary aphakia. Note the sliver/gray cornea. The ultrasound shows that no lens is present.

Iridotrabecular Dysgenesis: Primary Congenital Glaucoma

Most commonly caused by mutations in CYP1B1,39 mutations in LTBP240 have also been implicated in this disease. Treating the glaucoma causes reversal of the secondary corneal opacification (Fig. 13), but if the condition is neglected, then permanent stromal scarring accompanied by breaks in Descemet membrane may be seen.

FIGURE 13
FIGURE 13:
A case of primary congenital glaucoma. By controlling the glaucoma, the cornea should be allowed to clear. If we were to advocate keratoplasty as the first option, it would clearly be incorrect. Similarly, while we only have keratoplasty to offer children with CCO or NCO secondary to KILD, it may be that in the future, we will treat the primary problem, for example, lens malformation and provide keratoplasty.

Iridotrabecular Dysgenesis: ARA/Syndrome

ARA or Axenfeld–Rieger syndrome is caused by mutations in PITX2 or FOXC1.41 If a child has CCO and has marked posterior embryotoxon, then mutations in either of these genes may be causative. If a child has CCO usually bilateral, with no posterior embryotoxon but has extraocular features seen in Axenfeld–Rieger syndrome (maxillofacial hypoplasia, anomalous dentition, and paraumbilical hernia), then testing for PITX2 and FOXC1 should be entertained. Why most cases of ARA are not associated with CCO is unclear, but it is likely that a downstream effect of how these transcription factors interact affects the final phenotype. If a child has Axenfeld–Rieger syndrome and is short for age, the likely gene is PITX2 and the child needs magnetic resonance imaging to exclude pituitary axis problems, which have been reported in cases of PITX2 mutations.42 Perhaps of great note is the effect of digenic inheritance with these 2 genes leading to a very severe phenotype of CCO.43

Iridotrabecular Dysgenesis: Aniridia

In cases of complete absence of the iris due to mutations in PAX6, the lens may become apposed to the cornea leading to central corneal opacity (Fig. 10). Although this is a form of KILD, the etiology is the absence of iris due to the PAX6 mutation. Ancillary signs such as nystagmus, corneal pannus, foveal hypoplasia, and optic nerve hypoplasia all point to the diagnosis. If this is sporadic, then the possibility of a deletion causing this must be entertained and the possibility of Wilms tumor being present must be excluded because the gene for Wilm tumor (WT1) resides near PAX6 on chromosome 11p13. Renal ultrasound scan must be performed every 3 months until molecular diagnosis either confirms an intragenic mutation involving only PAX6 or a deletion syndrome is confirmed after which the patient would need lifelong surveillance for the possibility of developing Wilms tumor.

ACQUIRED SECONDARY CORNEAL DISEASE

These include infection, trauma, and metabolic disorders.

Infection

Viral and bacterial infections are the commonest, but fungal infections have been described in infants less than 4 weeks old.

Viral

One of the most common viral infections that affect the cornea in newborns is herpes simplex virus,44,45 with onset often within 2 weeks of birth. There is often a cloudy cornea with a large epithelial defect, and the diagnosis is made on corneal scrapes. Systemic pediatric evaluation is critical to exclude pneumonitis, hepatitis, and/or encephalitis.

Bacterial

Bacterial infection can result in significant corneal opacities46–48 (Fig. 9), and increasingly, deep anterior lamellar keratoplasty has been used instead of PKP to treat the residual scarring surgically.49

Trauma

Specific etiologies that should be kept in mind when a child presents with corneal opacity at birth include forceps injury and amniocentesis injury.

Forceps Injury

Corneal edema secondary to forceps injury during complicated childbirth is well recognized. The breaks seen are usually linear and almost always unilateral. Recently, the use of Descemet stripping automated endothelial keratoplasty has been advocated even as late as 8 years of age with improvement in visual acuity.50

Amniocentesis Injury

This is extremely rare but should be considered when there is a unilateral angular or linear opacity commensurate with a needle perforation. Suspicion should rise if there are concomitant signs such as cataract, iris or pupil abnormalities, or lid damage.

Metabolic Disorders

Although mucopolysaccharidoses, cystinosis, and other metabolic disorders are often cited as causes of CCO or NCO, there is only 1 condition that truly causes corneal clouding in newborns within a few weeks of birth.51 It is extremely rare, and the patient will often have other systemic abnormalities necessitating hospitalization.

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Keywords:

congenital corneal opacity; neonatal corneal opacity; corneal dystrophy; corneal dermoid; cornea plana; peripheral sclerocornea; iridocorneal adhesion; keratolenticular adhesion; primary aphakia; PAX6; FOXC1; PITX2; FOXE3; B3GALTL; ZEB1; SLC4A11; Peters anomaly; sclerocornea; forceps injury; primary congenital glaucoma; aniridia; Axenfeld–Rieger anomaly; Peters plus syndrome; MLS syndrome; MIDAS syndrome; encephalocraniocutaneous syndrome

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