Congenital clouding or opacification of the normally clear cornea can result from various genetic, metabolic, developmental, and idiopathic causes.
Early diagnosis is essential so that appropriate treatment can be initiated as early as possible and the child can obtain the best possible vision. Early ophthalmologic diagnosis can also facilitate recognition of an underlying systemic disorder.
A common reason for congenital clouding of the cornea is congenital glaucoma.
Other major causes of corneal clouding include the following:
The following is a frequently used 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 or opacity of the cornea include the following: corneal keloids, congenital corneal ectasia, congenital hereditary stromal dystrophy, posterior polymorphous dystrophy, and Fryns syndrome.
Causes of congenital corneal opacities may be classified as primary corneal disease or secondary corneal disease. Primary corneal disease is developmental and may be isolated to the cornea or have a related systemic component. Secondary corneal disease may be developmental or acquired from metabolic diseases, trauma, or infections.[1]
Sclerocornea
Sclerocornea is a congenital disorder of the anterior segment in which the cornea is opaque and resembles the sclera; the limbus is indistinct. Sclerocornea manifests as a nonprogressive noninflammatory 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.[2]
It has been argued that the term “sclerocornea” should be regarded only as a sign but not a diagnosis. Evaluation using ultrasound biomicroscopy (UBM) would better determine the presence of other anterior segment abnormalities such kerato-irido-lenticular adhesions.
Descemet membrane tears
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.
Forceps-induced obstetric trauma, with resultant Descemet membrane tears and corneal edema and clouding, is a cause of corneal clouding; it is almost always unilateral. 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.
Amniocentesis injury is extremely rare but should be considered in a patient with unilateral angular or linear opacity consistent with the appearance of a needle perforation. Lid damage and intraocular abnormalities such as cataract or iris or pupillary irregularity should raise suspicion.
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. Infectious keratitis may also be caused by bacterial or fungal infection.
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.
Central, paracentral, or complete corneal opacity is always present in patients with Peters anomaly. Patients with type 1 Peters anomaly have iridocorneal adhesions, and 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. Iridocorneal adhesions are often avascular, whereas keratolenticular adhesions are usually vascularized.
As with sclerocornea, the term “Peters anomaly” would be better regarded as a sign rather than a diagnosis, and ultrasound biomicroscopy evaluation should be performed for proper diagnosis and treatment planning.
Congenital hereditary endothelial dystrophy
Congenital hereditary endothelial dystrophy (CHED, formerly CHED2) is most likely only an autosomal-recessive disorder. The so-called autosomal-dominant–inherited CHED (formerly CHED1) is insufficiently distinct to continue to be considered a unique corneal dystrophy. On review of almost all published cases, the description appeared most similar to a type of posterior polymorphous corneal dystrophy linked to the same chromosome 20 locus (PPCD1).[3]
CHED manifests in infancy as a nonprogressive cloudiness of the cornea, light sensitivity, tearing, and, in some cases, nystagmus. Infants with CHED are usually comfortable despite sometimes having profound corneal swelling. There is diffuse corneal edema, thickening of the Descemet membrane, and paucity of endothelial cells.
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.[4]
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.[5]
Harboyan syndrome
Harboyan syndrome manifests with diffuse bilateral corneal edema and occurs with severe corneal clouding, blurred vision, visual loss, and nystagmus. It is a congenital hereditary endothelial dystrophy (CHED) joined with progressive, postlingual sensorineural hearing loss.
According to Desir, 24 cases from 11 families of various origins (eg, Asian Indian, South American Indian, Sephardi Jewish, Brazilian Portuguese, Dutch, Gypsy, Moroccan, Dominican) have been reported.[6]
Mutations in the SLC4A11 gene located at the CHED locus on band 20p13-p12 cause Harboyan syndrome, demonstrating that CHED and Harboyan syndrome are allelic disorders.
Corneal dermoids
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. Blepharoptosis, bilateral epibulbar dermoids, microphthalmia, epibulbar tumors, and retinal abnormalities have been documented in individuals with Goldenhar-Gorlin syndrome, also known as oculoauriculovertebral (OAV) dysplasia.
Dermoids may also be central and obstruct the visual axis.
The presence of corneal dermoid with an ipsilateral area of alopecia or nevus of the scalp should prompt MRI to evaluate for intracranial abnormalities and to diagnose encephalocraniocutaneous lipomatosis.[7]
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."[8] These scars seem to be related to an inappropriate repair response of the corneal tissue to trauma. They are also associated with Lowe syndrome.
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, and mutations in the decorin (DCN) gene have been implicated. Visual acuity is decreased. Strabismus and nystagmus may occur.
Posterior polymorphous dystrophy
Posterior polymorphous dystrophy (PPMD) 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. Bower has suggested that PPMD might be linked to Alport syndrome.[9] It rarely presents with corneal clouding at birth.
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.
Sanjad-Sakati syndrome
Sanjad-Sakati syndrome, also referred to as hypoparathyroidism-retardation-dysmorphism (HRD) syndrome, was reported as a cause of congenital clouding of the cornea in Oman.[10]
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. In a study published in 2013 of 26 patients with primary congenital glaucoma compared with 20 normal controls, corneal hysteresis and corneal resistance factor had a high correlation with central corneal thickness.[11] Researchers found that in primary congenital glaucoma, keratocyte density measured with vivo laser-scanning confocal microscopy decreased but did not impact corneal hysteresis and corneal resistance factor. In primary congenital glaucoma, mean endothelial density decreased but did not impact corneal hysteresis and corneal resistance factor. The average endothelial density also decreased in primary congenital glaucoma. They concluded that reduced central corneal thickness and increased corneal diameter were major ocular factors relating to the modified corneal biomechanical profile in primary congenital glaucoma, whereas cellular alterations in corneal endothelium and stroma and did not have a substantial biomechanical impact.
Peters anomaly can result from mutations in the PAX6 gene (11p13), the PITX2 gene (4q25-26), the CYP1B1 gene (2p22-21), and the FOXC1 gene (6p25),[12] 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. Congenital stromal corneal dystrophy development depends on extracellular deposition and export of truncated decorin.[13]
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.[14]
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.
A KERA mutation can be associated with cornea plana.[15]
Congenital corneal opacities (CCO) is estimated to affect 3 in 100,000 newborns. This number increases to 6 in 100,000 if patients with congenital glaucoma are included.[16]
United States
Corneal clouding, whether idiopathic or linked to a genetic syndrome, is uncommon in newborns.
In a study by Rezende et al 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%).[17] Seven eyes (9%) were classified as idiopathic.[17] 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 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.[18] 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 age 10 years. 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.[19]
In Japan, medical records of patients with congenital corneal opacities in relation to anterior segment dysgenesis seen in the National Center for Child Health and Development between April 2002 and October 2009 were retrospectively studied. Clinical diagnoses included Peters anomaly (72.7% of cases), anterior staphyloma (11.4%), Rieger anomaly (7.7%), sclerocornea (6.4%), and others (1.8%). Visual acuity was measured in 61 patients. The best-corrected visual acuity in the better eye of bilaterally involved patients was 20/60 to 20/1000 (low vision according to the International Classification of Diseases, Ninth Revision, Clinical Modification) in 43.2% of cases and less than 20/1000 (legally blind) in 24.3%. Fundus examination was performed in 82 eyes, and disorders were seen in 12 of 82 patients (14.6%). Systemic abnormalities were present in 35 of 139 patients (25.2%); 5 patients (3.6%) had a family history. Of the 160 eyes of 109 patients with Peters anomaly, 51 of 109 patients (46.8%) had bilateral Peters anomaly, 30 (27.5%) had fellow eyes that were normal, and 28 (25.7%) showed other abnormal ocular findings in the fellow eye.[20]
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.
The earlier keratoplasty is performed (generally prior to age 3-6 months), 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 have a poorer visual prognosis.
The prognosis for life depends on other systemic anomalies.
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 aids such as loupes and binoculars depending on their visual potential.
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.
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 (FAS), 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.[21]
Children with FAS may show a spectrum of eye abnormalities. External signs include short palpebral fissures, telecanthus, epicanthus, blepharoptosis, microphthalmos, and strabismus. Intraocularly, the most commonly detected signs include optic nerve hypoplasia and increased tortuosity of the retinal vessels.[22]
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.[23]
Congenital rubella
A cloudy cornea was observed in microphthalmic eyes in patients with congenital rubella.[24]
Clinical variant of Sanfilippo syndrome
A 4-month-old male infant had severe corneal opacity since birth.[25] 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 age 6 months. 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
Mucopolysaccharidoses can result in corneal clouding but do not necessarily manifest in the natal period.
In infants with congenital corneal clouding, systemic and ocular findings that accompany the corneal opacity allow for the syndromic classification of the infant's condition.
Peters anomaly is an uncommon syndrome that manifests as central or paracentral 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 of congenital corneal clouding are genetic, metabolic, developmental, infectious, and idiopathic.
Primary corneal disease is developmental and may be isolated to the cornea or have a related systemic component. Secondary corneal disease may be developmental or acquired. Developmental causes are those that affect the cornea-iris-lens axis (kerato-irido-lenticular dysgenesis) or those that affect the iris-angle axis (iridotrabecular dysgenesis). Acquired causes include infection, trauma, and metabolic disorders.
Diagnostic workup of a patient with congenital corneal clouding or opacity begins with a detailed maternal obstetric and perinatal history, family history, and systemic examination. A thorough ocular examination often requires general anesthesia with slit-lamp examination, measurement of corneal diameter and intraocular pressure, gonioscopy, refraction, and dilated fundus examination. A-scan, B-scan, and ultrasound biomicroscopy may also be required.
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.
The imaging studies below may be performed depending on the physical findings to assess for conditions that may accompany corneal clouding.
Photoscreening is designed to detect abnormalities in children's eyes, particularly abnormal refractive errors, which can lead to amblyopia. Photoscreening can also be used to detect congenital glaucoma. 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 (see image below), 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.
Gonioscopy can be performed with a Koeppe lens. IOP can be measured with an 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.
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. This includes patients with type II and VI mucopolysaccharidosis (MPS) in whom clinically marked corneal clouding is present; measuring the corneal thickness can evaluate intraocular pressure and possible coexistent glaucoma.[26]
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.[27]
B-scan ultrasonography is necessary to evaluate the posterior segment if the corneal opacity is dense and central.
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.
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.
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 depend on the etiology of the corneal clouding.
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."[8]
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.
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.
Histological examination of corneal keloids reveals thick collagen bundles haphazardly arranged, with focal areas of myofibroblastic proliferation.[12]
In dermoids and lipodermoids, the surface epithelium may or may not be keratinized. Bowman membrane is often 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.[8]
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 lines the posterior corneal stroma. Usually, no sign of an inflammatory infiltrate is present. Descemet's membrane and corneal endothelium are absent."[8]
In congenital hereditary stromal dystrophy or congenital stromal corneal dystrophy (CSCD), the epithelium is normal. Amorphous areas consisting of thin filaments randomly arranged in an electron-lucent ground substance separate lamellae of normal appearance.[3] Collagen fibril diameter is approximately half the normal size. The keratocytes and the endothelium are normal. The anterior banded zone of Descemet membrane may be absent.[12]
In congenital hereditary endothelial dystrophy (CHED), light microscopy shows diffuse epithelial and stromal edema, defects in the Bowman layer, degenerated corneal endothelium with multinucleated sparse and atrophic endothelial cells, and a thickened laminated Descemet membrane due to abnormal and accelerated secretion by the endothelial cells. Electron microscopy shows multiple layers of basement membrane–like material on the posterior part of Descemet membrane, degeneration of endothelial cells with many vacuoles, and stromal thickening with severe disorganization and disruption of the lamellar pattern.[3]
Posterior polymorphous corneal dystrophy (PPCD), formerly known as posterior polymorphous dystrophy, shows an endothelial cell layer with blebs, discontinuities, or reduplication. Descemet membrane has multiple layers of collagen on its posterior surface that manifest as focal fusiform or nodular excrescences.[3]
Treatment of congenital corneal clouding or opacity is primarily surgical. After surgery, treatment of amblyopia and optical therapy is helpful.
The future holds new treatments for clouding of the cornea. An interesting mouse study found a cure for corneal defects in mice with mucopolysaccharidosis type VII with transplantation of umbilical stem cells of the mesenchymal type from humans.[28]
For patients with bilateral and visually disabling corneal opacity, corneal transplantation or keratoplasty is recommended. To prevent amblyopia, the earlier the surgery is performed (generally prior to age 3-6 months), the better the results.
In patients with a dense unilateral opacity and a normal fellow eye, the decision to operate may be more difficult because, although the treatment is still surgical, the visual prognosis is guarded.
In children, keratoplasty is a high-risk transplantation. Indications for keratoplasty have increased with the improvement of surgical techniques and therapies. In children, keratoplasty 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.[29]
In one study, the overall success rate of graft clarity was 78% for children undergoing corneal transplantation for congenitally opaque corneas.[30] 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 performed simultaneous Ahmed glaucoma valve implantation and penetrating keratoplasty (PK) to manage refractory congenital glaucoma with corneal opacity.[31] 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.
Miller described an infant born with bilateral corneal clouding that was clinically diagnosed as congenital anterior staphyloma.[32] Peters anomaly was confirmed histopathologically and reflected one entity on the clinical spectrum of Peters anomaly. Miller 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.[32]
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.[33]
Frueh and Brown retrospectively assessed the prognosis and complications of corneal grafting in 58 infants and young children with congenital corneal opacities.[34] Preoperative diagnoses included sclerocornea (27 eyes), Peters anomaly (17 eyes), partial sclerocornea (12 eyes), and congenital glaucoma (2 eyes). PK was performed between age 5 days and 65 months 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).
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.
For patients with a clear peripheral cornea, peripheral optical iridectomy may be performed.
Myra Vita F Ocubillo, MD, DPBO, FPAO, Staff Ophthalmologist, ACES Eye Referral Clinics, Cebu Velez General Hospital, Perpetual Succour Hospital, University of Cebu Medical Center, St Vincent General Hospital, Philippines
Disclosure: Nothing to disclose.
Specialty Editors
Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Received salary from Medscape for employment. for: Medscape.
Christopher J Rapuano, MD, Professor, Department of Ophthalmology, Sidney Kimmel Medical College of Thomas Jefferson University; Director of the Cornea Service, Co-Director of Refractive Surgery Department, Wills Eye Hospital
Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: Cornea Society, AAO, OMIC, Avedro; Bio-Tissue; GSK, Kala, Novartis; Shire; Sun Ophthalmics; TearLab<br/>Serve(d) as a speaker or a member of a speakers bureau for: Avedro; Bio-Tissue; Shire<br/>Received income in an amount equal to or greater than $250 from: AAO, OMIC, Avedro; Bio-Tissue; GSK, Kala, Novartis; Shire; Sun Ophthalmics; TearLab.
Chief Editor
Hampton Roy, Sr, MD, Associate Clinical Professor, Department of Ophthalmology, University of Arkansas for Medical Sciences
Disclosure: Nothing to disclose.
Additional Contributors
Benjamin D Freilich, MD, FACS, Assistant Clinical Professor, Department of Ophthalmology, Icahn School of Medicine at Mount Sinai; Director of Retina Service, Bronx Veterans Administration Medical Center
Disclosure: Nothing to disclose.
Noah S Scheinfeld, JD, MD, FAAD, † Assistant Clinical Professor, Department of Dermatology, Weil Cornell Medical College; Consulting Staff, Department of Dermatology, St Luke's Roosevelt Hospital Center, Beth Israel Medical Center, New York Eye and Ear Infirmary; Assistant Attending Dermatologist, New York Presbyterian Hospital; Assistant Attending Dermatologist, Lenox Hill Hospital, North Shore-LIJ Health System; Private Practice
Disclosure: Nothing to disclose.
Richard W Allinson, MD, Associate Professor, Department of Ophthalmology, Texas A&M University Health Science Center; Senior Staff Ophthalmologist, Scott and White Clinic
Disclosure: Nothing to disclose.
Acknowledgements
Jonathan Freilich, MD, FACS Clinical Instructor, Department of Ophthalmology, Mount Sinai School of Medicine; Consulting Staff, Department of Ophthalmology, Mount Sinai Hospital, St Luke's Roosevelt Hospital Center
Congenital Corneal Opacities - Asia Pacific. American Academy of Ophthalmology. Available at https://www.aao.org/topic-detail/congenital-corneal-opacities-asia-pacific. Nov 2015; Accessed: Sept 2018.
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