Congenital Clouding of the Cornea Workup

• 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 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. 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.^[22]
  • 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.^[23]
  • 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.

• 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.
• 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.

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."^[7]

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.^[21] (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."^[7]

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."^[7]

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."^[7]

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."^[7]

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."^[7]

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."^[7]