AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Multimedia
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Multimedia
• References

Background

A variety of genetic, metabolic, developmental, and idiopathic causes can result in congenital clouding of the cornea. A common reason for congenital clouding of the cornea is congenital glaucoma. Other major causes of corneal clouding include the following:

• Birth trauma
• Peters anomaly
• Dermoid tumors (limbal dermoids)
• Sclerocornea
• Congenital hereditary endothelial dystrophy (CHED)
• Mucopolysaccharidoses
• Infectious/inflammatory processes

The following is a mnemonic for the causes of congenital clouding of the cornea:

• S - Sclerocornea
• T - Tears in the Descemet membrane secondary to birth trauma or congenital glaucoma
• U - Ulcers
• M - Metabolic
• P - Peters anomaly
• E - Edema (CHED)
• D – Dermoid

Other rarer causes of congenital clouding of the cornea include the following: cornea plana, corneal keloids, oculoauriculovertebral (OAV) dysplasia (Goldenhar-Gorlin syndrome), congenital corneal ectasia, congenital hereditary stromal dystrophy, posterior polymorphous dystrophy, and Fryns syndrome.

Sclerocornea

Sclerocornea is an uncommon developmental abnormality of the anterior segment due to mesenchymal dysgenesis. Sclerocornea manifests as a stationary congenital anomaly. It is usually seen as an isolated ocular abnormality involving both eyes, although it can occur unilaterally. This condition typically occurs sporadically but may also have a familial or autosomal dominant inheritance pattern.

On clinical evaluation, patients with partial sclerocornea have a peripheral, white, vascularized, 1- to 2-mm corneal rim that blends with the sclera, obliterating the limbus. The central cornea is generally normal. In total sclerocornea, the entire cornea is involved, but the center of the cornea is clearer than the periphery. This finding distinguishes it from Peters anomaly, in which the center is most opaque. The opacification affects the full thickness stroma and limits visualization of the posterior corneal surface and of the intraocular structures.

Histopathology reveals disorganized collagenous tissue containing fibrils that is larger than normal. Potential coexisting abnormalities include a shallow anterior chamber, abnormalities of the iris and the lens, and microphthalmos. Systemic abnormalities, such as limb deformities and craniofacial and genitourinary defects, can also accompany this finding. In generalized sclerocornea, early keratoplasty should be considered to provide vision, although the prognosis is guarded.¹

Descemet membrane tears

Forceps-induced obstetric trauma, with resultant Descemet membrane tears and corneal edema and clouding, is a cause of corneal clouding. This clouding is differentiated from primary congenital glaucoma (PCG) by the presence of periorbital soft tissue trauma, normal intraocular pressure (IOP), and the frequently vertical orientation of the Descemet membrane tears, and the absence of corneal enlargement, an abnormally deep anterior chamber, and an abnormal filtration angle.

Breaks in the Descemet membrane should be identified and differentiated from other abnormalities, such as the more vertically oriented defects seen after forceps-induced birth trauma or the irregularly scattered defects seen with posterior polymorphous dystrophy.

Corneal edema and haze are common signs of congenital glaucoma, as are horizontal or circumferential breaks in the Descemet membrane (termed Haab striae). Haab striae will remain visible on examination throughout the patient's life, even if the edema resolves with IOP normalization. Gonioscopic findings show a higher, flatter insertion of the iris at the level of the scleral spur, and the trabecular meshwork appears compacted.

Ulcers

Viral keratitis, such as herpetic keratitis or rubella keratitis, can result in a cloudy cornea in the newborn. Rubella keratitis in the newborn may particularly resemble PCG because it can be bilateral and associated with glaucoma.

Metabolic causes

Mucopolysaccharidoses

Mucopolysaccharidoses (MPS) can manifest with corneal clouding, including Hurler, Scheie, and Hurler-Scheie syndromes (all MPS I); Morquio syndrome (MPS IV); and Maroteaux-Lamy syndrome (MPS VI). Corneal clouding is not present in Hunter syndrome (MPS II) and Sanfilippo syndrome (MPS III).

Sphingolipidoses

For the most part, sphingolipidoses affect the retina, not the cornea, except in Fabry disease, an X-linked recessive disease. Fabry disease causes whorl-like opacities in the corneal epithelium (cornea verticillata), similar to those caused by chloroquine or amiodarone. Symptoms of Fabry disease also include skin lesions and peripheral neuropathy; renal failure is a common and serious complication.

Mucolipidoses

Mucolipidoses manifest with corneal clouding, in particular GM gangliosidosis type 1 and mucolipidoses types I and III.

Peters anomaly

Peters anomaly is not an isolated anterior segment abnormality; rather, it occurs as a diverse, phenotypically heterogeneous condition associated with several underlying ocular and systemic defects. Peters anomaly and PCG are genetically and phenotypically distinct conditions.

Central, paracentral, or complete corneal opacity is always present in patients with Peters anomaly. In usual cases, no vascularization of this opacity occurs; this feature helps in distinguishing it from other causes of congenital corneal opacity.

In Peters anomaly, central or paracentral corneal opacity is present. In some cases, this opacity may involve the entire cornea. In type 1, the lens may or may not be cataractous; however, the lens does not adhere to the cornea. In type 2, the lens is cataractous and adheres to the cornea. It is associated with defects in the PAX6 gene.

Congenital hereditary endothelial dystrophy

CHED manifests either in infancy or in young childhood with a cloudy cornea, light sensitivity, tearing, and sometimes nystagmus. An autosomal recessively inherited type of CHED usually appears at birth and is not progressive. Infants with this type of CHED are usually comfortable despite sometimes having profound corneal swelling. A dominantly inherited form of CHED occurs and is generally less severe than the autosomal recessive form in presentation. Youngsters with the dominantly inherited form usually present to the ophthalmologist by 2 years of age, when their parents begin to notice tearing, bright light sensitivity, and sometimes corneal haziness. No other ocular or systemic abnormalities are associated with either form of CHED.²

As stated, CHED is a corneal dystrophy characterized by diffuse bilateral corneal clouding resulting in impaired vision. It is inherited in an autosomal dominant or autosomal recessive manner. The autosomal dominant form of CHED has been mapped to the pericentromeric region of chromosome 20. Another endothelial dystrophy, posterior polymorphous dystrophy, has been linked to a large and overlapping region on chromosome 20.

A large, Irish, consanguineous family with autosomal recessive CHED was examined to determine if the disease was linked to this region. The technique of linkage analysis with polymorphic microsatellite markers amplified by polymerase chain reaction (PCR) was used. In addition, a DNA-pooling approach to mapping of homozygosity was used to demonstrate the efficiency of this method. Conventional genetic analysis in addition to a pooled-DNA strategy excluded linkage of autosomal recessive CHED to the autosomal dominant CHED and large loci for posterior polymorphous dystrophy.³

A clear association between congenital glaucoma and congenital hereditary endothelial dystrophy has been described in 3 patients. This combination should be suspected when persistent and total corneal opacification fails to resolve after bilaterally elevated IOP normalizes.⁴

Limbal dermoids

Sherman has extensively described limbal dermoids. Limbal dermoids are benign congenital tumors that contain choristomatous tissue (tissue not normally found at that site). They most frequently appear at the inferior temporal quadrant of the corneal limbus. However, they are occasionally present entirely within the cornea or confined to the conjunctiva. They may contain a variety of histologically aberrant tissues, including epidermal appendages, connective tissue, skin, fat, sweat gland, lacrimal gland, muscle, teeth, cartilage, bone, vascular structures, and neurologic tissue (including brain tissue). Malignant degeneration is extremely rare.

The most common system for classifying dermoids is based on their location and separates the lesions into 3 broad categories. The most common dermoid is the limbal dermoid, in which the tumor straddles the limbus. These are usually superficial lesions, but they may involve deep ocular structures. The second type involves only the superficial cornea, sparing the limbus, the Descemet membrane, and the endothelium. The third type involves the entire anterior segment in which the cornea is replaced with a dermolipoma that may involve the iris, the ciliary body, and the lens. Ultrasound biomicroscopy can be helpful in determining the extent and depth of the lesion.

Inheritance is usually sporadic, although autosomal recessive or sex-linked pedigrees exist. They can be associated with corneal clouding.

Although most limbal dermoids are isolated findings, approximately 30% are associated with Goldenhar syndrome, especially when they are bilateral.

Cornea plana

Cornea plana is an extremely rare, congenital hereditary malformation of the corneoscleral shape.⁵

Corneal keloids

Perry noted, "Corneal keloids are hypertrophic scars of the cornea that may be present at birth following intra-uterine trauma but more often appear spontaneously or after minor trauma in early childhood."⁶ These scars seem to be related to an inappropriate repair response of the corneal tissue to trauma. They are also associated with Lowe syndrome.

OAV dysplasia (Goldenhar-Gorlin syndrome)

Blepharoptosis, bilateral epibulbar dermoids, microphthalmia, epibulbar tumors, and retinal abnormalities have been documented in Goldenhar syndrome. Visual acuity is usually reduced and corneal clouding can occur.

Congenital corneal ectasia

Congenital corneal ectasia is an opaque, ectatic cornea extending between the lids and commonly occurring with corneal and lens clouding.

Congenital hereditary stromal dystrophy

Congenital hereditary stromal dystrophy manifests neonatally with a diffuse clouding of the central anterior corneal stroma with other normal corneal physical and nervous structures. The cornea is not edematous. It is nonprogressive. Its inheritance is autosomal dominant. Visual acuity is decreased. Strabismus and nystagmus may occur. The basic defect appears to be disordered fibrogenesis of stromal collagen.

Posterior polymorphous dystrophy

Posterior polymorphous dystrophy is a slowly progressive, uncommon, dominantly inherited condition. It is usually bilateral but sometimes asymmetric. It manifests with isolated or coalescent posterior corneal vesicular (the most distinctive characteristic), multilayered Descemet membrane thickening, and a bandlike configuration with sharp scalloped margin. It can cause progressive corneal edema and is associated with iris irregularities and glaucoma.

Fryns syndrome

First described in 1979, Fryns syndrome is a rare, generally lethal, autosomal recessive multiple congenital anomaly (MCA) syndrome. Patients with the syndrome present with the classical findings of cloudy cornea, brain malformations, diaphragmatic defects, and distal limb deformities.

Pathophysiology

Genetic, developmental, metabolic, and idiopathic factors are implicated as the pathophysiologic basis for congenital clouding of the cornea.

A common reason for congenital clouding of the cornea is congenital glaucoma.

Peters anomaly has been linked to genetic defects in the PAX6 gene, and a vascular-disruption sequence may be an important pathogenetic mechanism of the anomaly.

Congenital stromal dystrophy of the cornea caused by a mutation in the decorin gene has been noted and linked to congenital clouding of the cornea.

The autosomal dominant disorder Axenfeld-Rieger syndrome is associated with defects in the development of the eyes, teeth, and umbilicus. The eye manifests with iris ruptures, iridocorneal adhesions, cloudy corneas, and glaucoma. Transcription factors, such as PITX2 and FOXC1, carry point mutations that cause the disorder. Findings indicate a novel pathogenetic mechanism in which excess corneal and iridal PITX2A causes glaucoma and anterior defects that closely resemble those of Axenfeld-Rieger syndrome.

Mucopolysaccharidoses (the genetic defects of which have been elaborated elsewhere) are linked to congenital clouding of the cornea. In addition to mucopolysaccharidoses, the differential diagnosis of bilateral corneal stromal opacification includes diseases related to high-density lipoprotein (HDL) deficiency (eg, lecithin-cholesterol acetyltransferase [LCAT] deficiency, Tangier disease, fish-eye disease), Schnyder crystalline stromal dystrophy, cystinosis, gout, and mucolipidoses.

Cloudy cornea can result from congenital infections, such as rubella, and excess prenatal maternal consumption of alcohol.

Lumican and keratocan are members of the small leucine-rich proteoglycan (SLRP) family. They are the major keratan sulfate proteoglycans in the corneal stroma. Both lumican and keratocan are essential for normal cornea morphogenesis during embryonic development and maintenance of corneal topography in adults. This function is attributed to their bifunctional characteristic (protein moiety–binding collagen fibrils to regulate collagen fibril diameters and highly charged glycosaminoglycan [GAG] chains extending out to regulate interfibrillar spacings) that contributes to their regulatory role in extracellular matrix assembly.

In homozygous knockout mice, the absence of lumican leads to the formation of cloudy corneas due to an altered collagenous matrix characterized by large fibril diameters and disorganized fibril spacing. In contrast, keratocan knockout mice have thin but clear corneas with an insignificant alteration of the stromal collagenous matrix. Mutations of keratocan cause cornea plana in humans, which is often associated with glaucoma and corneal opacities.⁷

Congenital corneal ectasia is thought to be due to a failure of the embryonic mesoderm to migrate and form the corneal endothelium and stroma of the iris at approximately 7 weeks' gestation.

Frequency

United States

Corneal clouding, whether idiopathic or linked to a genetic syndrome, is uncommon in newborns.

In a study by Rezende et al (2004) at Wills Eye Hospital, among 78 cases of congenital corneal abnormalities, the most common primary cause was Peters anomaly (40%), followed by sclerocornea (18%), dermoid (15%), congenital glaucoma (7%), microphthalmia (4%), birth trauma, and metabolic disease (3%). Seven eyes (9%) were classified as idiopathic.⁸ Ten patients had systemic abnormalities associated with their ocular condition. Management was medical in 38 eyes (49%). Twenty-four eyes (31%) underwent only 1 penetrating keratoplasty (PK). Only 1 eye received a regraft during the follow-up period. Eight grafts failed during the follow-up period.

The frequency of Goldenhar syndrome is 1 case per 3500-25,000 births.

International

Bermejo and Martinez-Frias (1998) analyzed data from the Spanish Collaborative Study of Congenital Malformations (ECEMC) in 1,124,654 consecutive births to study congenital eye malformations from an epidemiologic standpoint.⁹ They also studied the frequencies and causal and clinical aspects. In all, 414 neonates had eye malformations, for an overall prevalence of 3.68 per 10,000 newborns. Most frequent (cases per 100,000) were anophthalmia and/or microphthalmia (21.34), congenital cataract (6.31), coloboma (4.89), corneal opacity (3.11), and congenital glaucoma (2.85).

Data from a study of 113 blind people in Mansoura, Egypt, highlighted the causes and risk factors for blindness, as well as the health and social care needs of the blind. In two thirds of patients, blindness occurred before 10 years of age. More than half the study population reported risk factors for blindness. Congenital causes accounted for almost half the cases. The most common causes of bilateral blindness were corneal opacities, cataract, and glaucoma.¹⁰

Mortality/Morbidity

Blindness results from corneal opacity and the occasionally associated cataracts and glaucoma. Amblyopia is common. Mortality may be increased because of systemic involvement, especially cardiac anomalies that are systemic manifestations of syndromes that include corneal clouding.

Race

No racial association is reported with the development of corneal clouding.

Sex

No sexual predilection is reported with congenital corneal clouding. However, corneal clouding from keloids is most common in persons with dark skin.

Age

Congenital corneal clouding is noted in the natal period.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Multimedia
• References

History

A variety of historical scenarios are described for congenital clouding of the cornea. For example, a milky quality of the cornea may be noted at birth, with a decreased responsiveness to light. The obstetrician or the pediatrician may be the first to observe these ocular properties. The neonate may be completely asymptomatic, or he or she may have other ocular or systemic anomalies. The mother might give a history of prenatal exposure to a pathogen.

• Trisomy 8: A finding described in several patients with trisomy 8 is a central corneal opacity, but data regarding the natural history of this finding are lacking. In 1 patient, the corneal opacity spontaneously improved.
• New syndrome: A new syndrome of hereditary congenital corneal opacities, cornea guttata, and corectopia was reported.¹¹
• Peters anomaly: A child might have a history of Peters anomaly. A boy, born at the gestational age of 39 weeks, had Peters anomaly in association with a ring 21 chromosomal abnormality. Dysmorphic features included low-set ears, hypoplastic mandible, delicate and dry skin, narrow and arched palate, wide-spaced nipples, and hypotonia. He also had a cloudy right cornea. Chromosomal analysis disclosed a ring 21 defect. The cornea had a paracentral, white opacity with a loss of posterior stroma and no adherence of the iris to the leukoma. IOP, the lens, and the posterior pole were normal.¹²
• Maternal alcohol abuse: Three of 4 siblings born to parents with a history of heavy alcohol abuse had bilateral diffusely cloudy corneas at birth. The three siblings, who had mild systemic features of fetal alcohol syndrome, underwent corneal transplantations, and their specimens were examined under light and electron microscopy. On histology, alterations in the Bowman layer ranged from thickening to total loss. Various degrees of corneal stromal edema were observed. The unique pathologic feature in the corneas was the anomaly of the anterior banded zone of the Descemet membrane, which was absent, poorly formed, or thinned in the central and peripheral cornea. The corneal endothelium was attenuated or multilayered. The diffuse clouding and the range of histologic abnormalities in the corneas might have been related to the maternal alcohol abuse.¹³
• De Barsy syndrome
• • A male newborn had bilateral congenital corneal opacification. Examination revealed a variety of dysmorphic features, including cutis laxa, progeroid aspect, short stature, multiple hyperextensible subluxated joints, muscular hypotonia, and hyperreflexia. Bilateral penetrating keratoplasties were performed. Histopathologic examination revealed diffuse epithelial thickening, loss of the Bowman layer, and stromal attenuation with anterior stromal scarring. Special stains showed no deposition of abnormal material in the corneas. Electron microscopy demonstrated absence of the Bowman layer differentiation with a paucity of collagen fibers and extensive small, elastic fibers in the anterior stroma. The diagnosis was De Barsy syndrome, a rare, progeroid syndrome associated with characteristic ocular, facial, skeletal, dermatologic, and neurologic abnormalities.
  • De Barsy syndrome should be included in the differential diagnosis of congenital corneal opacification; its distinctive clinical features enable the clinician to easily differentiate it from other causes of congenital cloudy corneas.¹⁴
• Congenital rubella: A cloudy cornea was observed in microphthalmic eyes in patients with congenital rubella.¹⁵
• Clinical variant of Sanfilippo syndrome
• • A 4-month-old male infant had severe corneal opacity since birth.¹⁶ Examination revealed buphthalmos, increased IOP, and corneal opacity with neovascularization but not a dysmorphic face or hirsutism. The liver and spleen were impalpable. Hypotonia, poor head control, and absence of Moro and grasping reflexes were noted. He had no evidence of congenital infection (toxoplasmosis, other infections, rubella, cytomegalovirus infection, and herpes simplex [TORCH] study). Urine and plasma amino acid levels were normal. However, thin-layer chromatography showed excessive urinary excretion of heparan sulfate. Corneal transplantation was performed at 6 months of age. Histopathology of the corneal button showed homogeneous thickening of the Bowman layer and pinkish intracytoplasmic substances in the corneal stroma. The Alcian blue stain was positive, consistent with MPS of the cornea.
  • The manifestation in this case may be a clinical variant of Sanfilippo syndrome (MPS III).
• Mucopolysaccharidoses can result in corneal clouding but do not necessarily manifest in the natal period.

Physical

Central, paracentral, or complete corneal opacity is always present in infants with congenital corneal clouding. Systemic and ocular symptoms that accompany the clouding allow for the syndromic classification of the infant's condition.

• Peters anomaly is an uncommon syndrome that manifests with corneal clouding. (See also Peters Anomaly.) 
• • In type 1 Peters anomaly, 80% of cases are bilateral. Central or paracentral annular corneal opacity is present. The surrounding peripheral cornea may be clear or edematous because of glaucoma. The cornea is avascular. Iris strands often extend from the collarette, across the anterior chamber, to the posterior surface of the cornea. These strands may be filamentous or thick strands or sheets. A defect in the underlying corneal endothelium and the Descemet membrane causes the opacity. The lens may be clear or cataractous.
  • In type 2 Peters anomaly, cases are usually bilateral. The corneal opacity is dense and may be central or eccentric. The lens is usually cataractous and typically juxtaposed to the cornea. The posterior stroma, the Descemet membrane, and the endothelium are defective. Iris strands may or may not be present. Other ocular and systemic abnormalities are more common in type 2 than in type 1.
• Corneal clouding, as observed by using a slit lamp, may be used in the differential diagnosis of mucopolysaccharidoses. Corneal clouding is present in MPS I, VI, and VII but absent in MPS II.

Causes

Causes of congenital corneal clouding are genetic, metabolic, developmental, infectious, and idiopathic.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Multimedia
• References

Other Problems to be Considered

Posterior keratoconus
Sclerocornea
Intrauterine keratitis
Mucopolysaccharidoses
Congenital hereditary endothelial dystrophy
Corneal dermoids
Posterior polymorphous dystrophy
Cornea plana
Corneal keloids
Goldenhar syndrome
Congenital corneal ectasia
Congenital hereditary stromal dystrophy
Congenital hereditary endothelial dystrophy
Posterior polymorphous dystrophy
Fryns syndrome
Lowe syndrome

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Multimedia
• References

Lab Studies

• Corneal clouding is a clinical and not a laboratory finding unless it is due to mucopolysaccharidoses.
• If MPS VI is suspected, quantification of glycosaminoglycans (GAGs) in the urine and measurement of N-acetylgalactosamine-4-sulfatase (ARSB) activity in leukocytes may be warranted.
• In addition to the mucopolysaccharidoses, the differential diagnosis of bilateral corneal stromal opacification includes HDL-deficiency diseases (eg, LCAT deficiency, Tangier disease, fish-eye disease), Schnyder crystalline stromal dystrophy, cystinosis, gout, and mucolipidoses. Scheie syndrome (MPS I S) may easily be detected by finding alpha-L-iduronidase deficiency in leukocytes and increased mucopolysaccharide levels in the urine.

Imaging Studies

• The following imaging studies may be performed depending on the physical findings to assess for conditions that may accompany corneal clouding:
• • Newborn PCG can be recognized at birth because of the associated corneal opacification. The evaluation of congenital glaucoma should include the following: a complete eye examination, including anterior segment evaluation, with slit lamp biomicroscopy, funduscopy, tonometry, and gonioscopy. Ocular examination of a patient with congenital glaucoma can reveal anterior segment abnormalities of the cornea, iris, and filtration angle as well as related elevated IOP. A-scan ultrasonography can reveal an enlarged globe (buphthalmos). Genetic analysis can be done to detect syndromes associated with congenital glaucoma.
  • Indirect gonioscopy can be performed with a Goldmann lens. IOP can be measured with a Goldmann applanation tonometer. Photographs can be taken of the anterior segment and all 4 quadrants of the iridocorneal angle to record the presence of abnormalities. The iridocorneal angle can be graded according to the classification proposed by Spaeth.
  • Photoscreening is designed to detect abnormalities in children's eyes, particularly abnormal refractive errors, which can lead to amblyopia. Photoscreening can also detect congenital glaucoma.
  • Tonometry is an essential component of the examination but can be the most difficult part of the examination with a fractious child.
  • Inspection and examination of the anterior segment are facilitated by the use of a penlight and a handheld slit lamp, which allow maneuverability regardless of the child's position.
  • The optic nerve head may be examined with a direct or indirect ophthalmoscope.
  • MRI of the abdomen is indicated to rule out genitourinary abnormalities.
  • MRIs of the brain and spinal cord are also indicated to rule out neurologic defects.
  • Echocardiography is indicated to rule out cardiac defects.
  • Ocular ultrasonography may be useful in assessing other ocular abnormalities.
  • Ultrasound biomicroscopy (UBM) is often helpful in the evaluation of anterior segment structures that cannot be observed clearly because of the corneal opacity. UBM and histopathology can play a role in the evaluation of sclerocornea.¹⁷
  • B-scan ultrasonography is necessary to evaluate the posterior segment if the corneal opacity is dense and central.
  • CT scanning is indicated to help diagnose protuberant congenital corneal opacities.

Other Tests

• Hearing tests may be performed to rule out hearing abnormalities.
• Corneal clouding, as observed by using a slit lamp, may be used in the differential diagnosis of mucopolysaccharidoses. Corneal clouding is present in MPS I, VI, and VII but absent in MPS II.

Procedures

• Maroteaux-Lamy syndrome (MPS VI) can be evaluated by means of slit lamp biomicroscopy, Orbscan II slit scanning elevation topography, and in vivo confocal microscopy.
• Slit lamp biomicroscopy can reveal bilateral, altered corneal transparency involving the posterior half of the stroma.
• Funduscopy reveals bilateral small, crowded optic discs, and radial macula retinal folds.
• On in vivo confocal microscopy, the middle and posterior stroma can be visualized and show well-defined, unusually shaped keratocytes. These cells contain single or several hyporeflective regions with well-defined borders 1-11.6 micrometers in diameter. These abnormal keratocytes are particularly abundant in the posterior stroma and sparse in the anterior stroma.

Histologic Findings

Histopathologic results are often diagnostic for Peters anomaly. Histologic findings show either thinning or absence of the Descemet membrane or the endothelium. The lens may be normal, or it may be cataractous and adhere to the cornea. The stromal lamellae are irregular and more closely packed. Undifferentiated iris strands attach to the posterior surface of the cornea.

Perry states, "Histopathologic findings include absence of Descemet's membrane, corneal endothelium, and, usually, Bowman's membrane, as well as thinning of corneal stroma. The defects in Descemet's membrane, although usually single and central, may be multiple and isolated to the periphery, or they may be limited to an area of adhesion of iris. Descemet's membrane has been found to have embryonal ultrastructural characteristics combined with attenuated endothelium. The corneal stromal lamellae are more irregular and closely packed when compared to normal stromal lamella."⁶

Histochemical studies have shown absence of keratan sulfate in both the cornea and the sclera.

Immunohistochemical studies have shown increased amounts of fibronectin and type VI collagen in the corneas of patients with Peters anomaly.

In MPS VI B, the histopathologic and ultrastructural features of the corneal button reveal the accumulation of membrane-bound vacuoles containing fibrillogranular and lamellated material in keratocytes and endothelial cells and thinning of the Descemet membrane with excrescences. Other MPS diseases can have other histologic findings.

A 4-month-old male infant with severe corneal opacity since birth had buphthalmos, increased IOP, and corneal opacity with neovascularization.¹⁶ (See Clinical variant of Sanfilippo syndrome in History.) Histopathologic examination of the corneal button showed homogeneous thickening of the Bowman layer and pinkish intracytoplasmic substances in the corneal stroma. The Alcian blue stain was positive, consistent with MPS of the cornea. The manifestation of this case may be a clinical variant of Sanfilippo syndrome (MPS III).

In sclerocornea, the numbers of collagen fibrils are increased and their diameter varies in the normal corneal stroma. The Descemet membrane appears thin. Scleralization of the collagen fibrils often stops in the pre-Descemet membrane region, permitting deep lamellar keratoplasty.

In cornea plana, the corneal tissue is histologically normal. The axial length of eyes that contain cornea plana is normal.

Perry notes that, in corneal keloids, "Stromal nodules are composed of proliferating myofibroblasts, activated fibroblasts, and haphazardly arranged fascicles of collagen. Immunohistochemical stains show spindle cells that express immunoreactivity for vimentin and alpha smooth muscle actin. Keloid formation may be the result of excessive local delivery of amino acids and unknown noxious substances through leaking corneal vessels."⁶

Perry notes that, in corneal dermoids, "Histologically, the corneal epithelium may be keratinized. Bowman's membrane often is absent. The stroma is replaced to a variable degree by irregularly arranged, dense, vascularized, collagenous connective tissue containing hair follicles, hair shafts, sebaceous glands, fat, smooth muscle, striated muscle, cartilage, teeth, or bone. The mass may be either cystic or solid."⁶

Perry notes that, in congenital corneal ectasia, "Histologically, the corneal epithelium has normal thickness but may be keratinized secondary to exposure. Often, local attenuation of Bowman's membrane occurs. The stroma is thickened, disorganized, hypercellular, and vascularized. A double layer of pigment-containing cells line the posterior corneal stroma. Usually, no sign of an inflammatory infiltrate is present. Descemet's membrane and corneal endothelium are absent."⁶

Perry notes that, in congenital hereditary stromal dystrophy, "The collagen of the corneal stroma by electron microscopy consists of alternating layers of small-diameter collagen fibrils of approximately one-half the normal fibril diameter. Also, the anterior banded portion of Descemet's membrane is poorly developed. The endothelium is normal."⁶

Perry notes that, in congenital hereditary endothelial dystrophy, "Histologically, increased diameter of stromal collagen fibrils may produce a thick cornea. Descemet's membrane is thickened in a manner similar to that found with Fuchs' endothelial dystrophy, implying a corneal endothelial abnormality."⁶

In posterior polymorphous dystrophy, Perry notes that, histologically, "Descemet's membrane may be focally or diffusely thickened. Endothelial cells are multilayered and have desmosomes and intracytoplasmic filaments that are characteristic of epithelial cells. A layer of cells may be present beneath the corneal epithelium, but epithelial edema is not common. Iridocorneal adhesions, glassy membranes, and pupillary ectropion, which are changes found in the iridocorneal endothelial syndrome, also may be present in this condition."⁶

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical Care

Treatment is primarily surgical.

• After surgery, treatment of amblyopia and optical therapy can be helpful.
• In patients with MPS I, treatment with recombinant human alpha-L-iduronidase reduces lysosomal storage in the liver and ameliorates some clinical manifestations of the disease.

Surgical Care

For patients with bilateral and visually disabling corneal opacity, PK is recommended. To prevent amblyopia, the earlier the surgery is performed (generally prior to 3-6 months of age), the better the results.

In children, PK is a high-risk transplantation. Indications for PK increased with the improvement of surgical techniques and therapies. In children, PK allows for satisfying anatomical success but moderate visual improvement. Amblyopia is the major obstacle to success in children undergoing corneal grafting.

Surgical techniques for children differ from those used in adults because of the reduced ocular rigidity encountered in infants and young children. Use of a multispecialty team approach is important to improve the patient's visual outcome. Poor prognostic indicators include bilateral disease, concomitant infantile glaucoma, lensectomy and vitrectomy at the time of surgery, previous graft failure, extensive goniosynechiae, and extensive corneal vascularization. Prompt postoperative optical rehabilitation, combined with occlusion therapy when appropriate, is an important determinant of success.¹⁸

• In 1 study, the overall success rate of graft clarity was 78% for children undergoing corneal transplantation for congenitally opaque corneas.¹⁹ Best results were achieved in patients with posterior polymorphous dystrophy, followed by patients with Peters anomaly. Sclerocornea and congenital glaucoma were associated with a 50% likelihood of success, with repeated transplants needed in many of the eyes.
• Al-Torbak (2004) performed simultaneous Ahmed glaucoma valve implantation and PK to manage refractory congenital glaucoma with corneal opacity.²⁰ Twenty eyes of 17 patients were studied.
• • The most common cause of glaucoma failure that required subsequent surgery was subconjunctival scarring, which resulted in loss of long-term IOP control. Main graft-related complications included failure (13 of 20 eyes) and graft ulceration (6 of 20 eyes). In 4 of 6 ulcerated grafts, Streptococcus pneumoniae was cultured.
  • Subsequent surgery was the only significant clinical factor associated with poor outcome of glaucoma. However, a low graft survival rate was significantly associated with delinquency of follow-ups, corneal ulcers, subsequent surgeries, and postoperative complications.
  • The long-term success of simultaneous Ahmed glaucoma valve implantation and PK in refractory congenital glaucoma associated with corneal opacity is low, and the complication rate is high.
• For patients with a clear peripheral cornea, peripheral optical iridectomy may be performed.
• Miller (2003) described an infant born with bilateral corneal clouding that was clinically diagnosed as congenital anterior staphyloma.²¹ Peters anomaly was confirmed histopathologically and reflected one entity on the clinical spectrum of Peters anomaly. Miller (2003) detailed the patient's clinical course and histopathologic findings, as well as the unique surgical approach to corneoscleral grafting that was used to preserve the right globe.²¹  
• Primary combined trabeculotomy-trabeculectomy is a feasible surgical option in infants who have cloudy corneas at birth as a result of congenital glaucoma. The procedure was associated with a favorable visual outcome and a low rate of anesthetic complications in an Indian population.²²
• Frueh and Brown (1997) retrospectively assessed the prognosis and complications of corneal grafting in 58 infants and young children with congenital corneal opacities.²³
• • Preoperative diagnoses included sclerocornea (27 eyes), Peters anomaly (17 eyes), partial sclerocornea (12 eyes), and congenital glaucoma (2 eyes). PK was performed between 5 days and 65 months of age with a mean follow-up of 40 months (standard deviation, 29).
  • The overall success (including repeat grafts) was 70% for eyes with sclerocornea, 83% for those with partial sclerocornea, and 100% for those with Peters anomaly. However, 23 eyes had to be regrafted 2 weeks to 110 months after the first surgery.
  • The probability of maintaining a clear graft, calculated in survival analysis, was 75% (standard error, 6%) at 1 year and 58% (7%) at 2 years for the entire group. Complications included cataract development (12 eyes), secondary glaucoma (14 eyes), epithelial defects (6 eyes), band keratopathy (5 eyes), retinal detachment (3 eyes), wound leakage (2 eyes), retrocorneal membrane (1 eye), and microbial keratitis (2 eyes).
  • Therefore, corneal grafting for congenital opacities in infants has an excellent potential for long-term survival and should be performed as early as possible for unilateral or bilateral involvement. The postoperative course is complex, and regrafting is often required.
• In patients with MPS, corneal transplantation does not permanently resolve the problem.
• A 15-year-old male adolescent had Sly disease, a rare MPS caused by a deficiency of beta-glucuronidase and progressive bilateral corneal opacification. He received complete medical, genetic, and ophthalmic evaluation followed by PK. The cornea has remained clear for 2 years after surgery. Histopathology of the corneal button demonstrated vacuoles and granular inclusions consistent with this lysosomal storage disease.

Consultations

• Pediatrician - Thorough examination to rule out other systemic abnormalities
• Geneticist - Genetic counseling
• Vitreoretinal surgeon - Lensectomy and/or vitrectomy
• Cornea specialist - Keratoplasty
• Pediatric ophthalmologist – Amblyopia therapy
• Low-vision specialist - Management of poor vision, provision of optical aids

FOLLOW-UP

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Multimedia
• References

Further Outpatient Care

• An ophthalmologist should provide regular follow-up care for patients with graft rejection.
• In addition, a pediatrician should monitor patients for other congenital anomalies.
• Patients should receive visual rehabilitation as needed.
• A pediatric contact lens specialist should fit patients with aphakic contact lenses.

In/Out Patient Meds

• Medications may be indicated for treatment after corneal transplantation.

Complications

• Complications of corneal transplantation are varied.

Prognosis

• The visual prognosis is guarded.
• The earlier keratoplasty is performed (generally prior to 3-6 months of age), the better the likelihood of preventing deprivation amblyopia.
• • In most series, visual acuity in patients after keratoplasty was 20/80 or worse. Some investigators reported visual acuity of 20/40 in patients.
  • Also, in most series, the likelihood that patients maintain a clear graft was 30-50% at 10 years.
• Patients with glaucoma and cataract had a worsened prognosis.
• The prognosis for life depends on other systemic anomalies.

Patient Education

• Children with Peters anomaly and other genetic syndromes associated with corneal opacities require special educational assistance depending on their visual outcome. A low-vision specialist should evaluate these children.
• Patients may need loupes and binoculars depending on their visual potential.

MISCELLANEOUS

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical/Legal Pitfalls

• Failure to perform an evaluation under anesthesia in a timely fashion if an adequate examination cannot be performed in the office
• Failure to differentiate Peters anomaly from other conditions that mimic it
• Failure to refer the patient to other specialists to rule out systemic anomalies
• Failure to provide regular follow-up care for children with graft rejection or glaucoma
• Failure to offer visual rehabilitation

Special Concerns

• Cases of congenital corneal clouding and Peters anomaly have been reported to occur with fetal alcohol syndrome.
• Drinking during pregnancy should be discouraged.

MULTIMEDIA

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Multimedia
• References

Media file 1:  Clouding of the cornea since childhood.
	View Full Size Image
Media type:  Photo

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Multimedia
• References

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Article Last Updated: Jun 10, 2008