Congenital Clouding of the Cornea

Updated: Mar 10, 2023
  • Author: Melody Ana Tequillo Tan Daclan, MD; Chief Editor: Hampton Roy, Sr, MD  more...
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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:

  • Birth trauma

  • Dermoid tumors (limbal dermoids)

  • Sclerocornea

  • Congenital hereditary endothelial dystrophy (CHED)

  • Mucopolysaccharidoses

  • Infectious/inflammatory processes

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 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 usually is 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 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 as 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.


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 also may be caused by bacterial or fungal infection.

Metabolic causes


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).


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 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.


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]


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.


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


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


Congenital corneal clouding is noted in the natal period.



The visual prognosis is guarded.

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.


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 aids such as loupes and binoculars depending on their visual potential.