Causes of primary neonatal corneal opacification include congenital hereditary endothelial dystrophy (CHED), posterior polymorphous corneal dystrophy, congenital hereditary stromal dystrophy (CHED), and corneal dermoid. Secondary causes include trauma (e.g., forceps), infection, metabolic disorders, and congenital glaucoma. Corneal opacification requires further workup to diagnose the underlying cause and to help plan any surgical intervention.
Primary megalocornea is defined as a horizontal corneal diameter of >12 mm at birth or >13 mm by 2 years of age in the absence of elevated eye pressure. Congenital glaucoma must be ruled out; isolated cases do not usually require intervention. Microcornea is defined as a clear cornea of normal thickness with a horizontal corneal diameter of <9 mm in newborns and <10 mm after 2 years of age. It is commonly associated with other ocular and/or systemic findings.
Developmental anomalies of the iris include diffuse underdevelopment (congenital aniridia, including its association with Wilms tumor), focal developmental defects (coloboma), failed involution of the central iris (prepupillary membrane), iris cysts (and their association with thoracic aortic aneurysm), bilateral hypopigmentation (e.g., albinism), asymmetric pigmentation (heterochromia, e.g., Waardenburg syndrome, congenital Horner syndrome), iris atrophy (e.g., Axenfeld-Rieger anomaly), and displaced pupil (corectopia) with or without lens displacement (ectopia lentis), both of which can occur in isolation or in association with systemic causes such as neonatal Marfan syndrome.
Cornea: Abnormal Appearance or Size
Congenital Corneal Opacification (CCO)
Primary congenital corneal opacifications include congenital hereditary endothelial dystrophy (CHED), posterior polymorphous corneal dystrophy, congenital hereditary stromal dystrophy (CHSD), and corneal dermoids.
CHED manifests as bilateral, often symmetric, diffuse corneal cloudiness from edema ( Fig. 64.1 ). CHED1 (which is now known as CHED) usually presents with clear corneas at birth that tend to become progressively cloudier during the neonatal period, along with new-onset light sensitivity but no nystagmus. By contrast, CHED2 (which is now considered a neonatal variant of posterior polymorphous corneal dystrophy) usually presents with corneal cloudiness from birth that is nonprogressive and with nystagmus (due to lack of visual input from birth) but no light sensitivity. CHED may also be seen as part of Harboyan syndrome, which presents with CCO and sensorineural deafness.
CHSD presents with limbus-to-limbus corneal clouding and flake-like opacities in the corneal stroma but no corneal vascularization. Corneal dermoids are choristomas (normal cells in an abnormal location) and present as creamy nodular opacities that are classically located at the periphery of the cornea, where they can cause significant visual impairment from astigmatism. Sometimes they can obstruct the visual axis directly or cause ocular surface dryness and thinning (dellen) from tear film disruption.
Peters’ anomaly ( Fig. 64.2 ) and “sclerocornea” ( Fig. 64.3 ) have historically been used to describe certain types of CCO, although these terms are now discouraged due to their nonspecific nature. Because many prior reports utilize such terms, it is still important to note that Peters’ anomaly traditionally refers to abnormal adhesions between the cornea and iris (and is one form of anterior segment dysgenesis [ASD]). This impairs the ability of the inner layer of the cornea (endothelium) to successfully pump fluid out of the cornea in areas of adhesion, the process it uses to maintain clarity. As a result, Peters’ anomaly typically presents with cloudiness in part of the cornea from birth, which often slowly improves over a matter of months to years. Some cases also involve the lens and have congenital cataract. Peters’ plus syndrome includes additional systemic features such as short disproportionate stature, developmental delay, dysmorphic facial features, and cardiac, genitourinary, and central nervous system malformations.
Sclerocornea describes a nonprogressive, noninflammatory ingrowth of opaque sclera extending into the peripheral cornea, causing an indistinct border between the two tissues. It can occur in isolation or along with other ASD syndromes such as Peters’ anomaly. It can be complete, where the whole cornea is opaque and flattened, or it can spare the central cornea and only affect the peripheral part.
Mucolipidosis IV is the only true metabolic cause of neonatal CCO. This rare metabolic storage disease is inherited in an autosomal recessive pattern and is associated with progressive psychomotor retardation.
Acquired corneal opacification that presents early in life includes trauma from accidental or nonaccidental causes. Forceps injury should be kept in mind because this is a well-recognized etiology of postnatal corneal opacification. It is almost always unilateral and is associated with fine streaks (breaks) in the inner cornea, which are only visible with magnification. Viral or bacterial infection may both present with corneal clouding in the neonatal period , but are often accompanied by other findings such as eyelid swelling, corneal ulcer, and/or muco-purulent discharge. Corneal clouding also occurs as part of primary congenital glaucoma (discussed in the glaucoma chapter).
CCO has a prevalence of 3 in 100,000 newborns, or 6 in 100,000 when congenital glaucoma is included. Many of the primary forms are inherited. CHED can be passed on in an autosomal dominant (CHED1) or autosomal recessive (CHED2) manner. , Primary dysfunction of the corneal endothelium increases permeability, causing hydration by aqueous humor and hence clouding. Harboyan syndrome is due to mutations in SLC4A11 . CHSD is caused by disruption of collagen organization due to mutations in DCN (which encodes decorin). , Peters’ anomaly can occur sporadically, but dominant and recessive forms have been reported. It can be caused by mutations in PAX6 , PITX2 , FOXC1 , CYP1B1 , MAF , or MYOC and is associated with trisomy 13. Peters’ plus syndrome is recessively inherited and can be caused by mutations in B3GALTL. , Causes of sclerocornea show significant overlap with other forms of ASD and include mutations in FOXE3 , RAX , SOX2 , PITX3 , PAX6, and PXDN. Mucolipidosis type IV is caused by mutations in MCOLN1 ; mucolipin-1 dysfunction impairs lipid and protein transport, causing their accumulation in lysosomes. Viral infection early in the neonatal period is often caused by herpes simplex. When accompanied by purulent discharge, Neisseria gonorrhea should be considered due to the high rate of progression and risk of perforation.
Diagnosing the cause of neonatal CCO based on clinical appearance alone is hard, because different entities present similarly. High eye pressure helps distinguish primary congenital glaucoma from other causes. Corneal thickness measurement by pachymetry helps distinguish CHED (increased due to edema) from CHSD (normal thickness). Imaging using ultrasound biomicroscopy (UBM) and anterior segment optical coherence tomography (AS-OCT) helps identify cornea-iris or cornea-lens adhesions suggestive of Peters’ anomaly and also aids in preoperative planning. Genetic testing can help identify underlying genetic etiologies. Corneal lesions suspicious for infectious causes must be scraped and sent for microbiologic testing.
Primary corneal diseases without significant ASD can undergo full thickness corneal transplant (penetrating keratoplasty [PKP]) and have fair outcomes, albeit not as good as adults. For disorders that only affect specific layers of the cornea (e.g., CHSD), selectively transplanting that layer (i.e., deep anterior lamellar keratoplasty [DALK]) may be an option. Corneal dermoids can be managed by PKP or DALK, depending on their size. , Corneal transplants are avoided in patients with active infection, but once the infection and associated inflammation have resolved, the residual scar can be replaced with a PKP or DALK. , Conjunctival transplantation may help corneal clouding due to mucolipidosis IV.
Examples of disorders with corneal crystal deposits include cystinosis and tyrosinemia type 2. Crystals appear as bifringent stromal opacities that may be visually significant. Patients can have light sensitivity due to light scattering by the crystals or redness and irritation from an uneven corneal surface. Fifty percent of infants with cystinosis present with light sensitivity. Tyrosinemia type 2 can also present with corneal epithelial defects that resemble herpes simplex dendrites (pseudodendrites).
Cystinosis occurs in 1 in 100,000 newborns. There is no gender or racial predilection. It is the most common cause of pediatric renal Fanconi syndrome and accounts for 5% of pediatric renal failure cases. It is divided into three types, including nephropathic, intermediate, and nonnephropathic (ocular) forms ( Fig. 64.4 ). The nephropathic form is the most common and severe form and develops in infancy; it presents with light sensitivity and renal failure. The nonnephropathic form only affects the cornea.
Tyrosinemia type 2 results from elevated blood tyrosine levels, and affects the eyes, skin, and intellectual development. Symptoms include eye pain, redness, excess tearing, and light sensitivity as well as painful skin lesions on the palms and soles (palmoplantar hyperkeratosis). Fifty percent of patients have intellectual disability.
Cystinosis is inherited in an autosomal recessive manner. All forms are caused by mutations in CTNS , which encodes lysosomal membrane protein cystinosin. Impaired cystinosin function results in lysosomal cysteine accumulation due to impaired export; the accumulated crystals damage affected tissues.
Tyrosinemia type 2 is inherited in an autosomal recessive manner. It is caused by mutations in the gene tyrosine aminotransferase (TAT) ; this results in impaired function of the enzyme tyrosine aminotransferase, one of the enzymes required for tyrosine breakdown. Impaired tyrosine aminotransferase function causes accumulation of tyrosine crystals in affected tissues.
White blood cell cysteine levels of 3 to 20 nmol half-cysteine/mg protein is diagnostic of cystinosis. Molecular testing for mutations in the gene Cystinosin, Lysosomal Cystine Transporter (CTNS) can be performed. AS-OCT shows hyperreflective and iridescent deposits involving the corneal epithelium and corneal stroma but typically sparing the inner corneal layers. , Tyrosinosis is confirmed by high urinary elimination of tyrosine and tyrosine derivatives and high serum tyrosine levels up to 52 mg/100 mL.
In cases where corneal deposition is nonprogressive, complaints of light sensitivity may decrease over time, so observation is reasonable. Oral cysteamine treatment depletes systemic cysteine levels and is used to improve renal function; of note, it does not help with corneal crystal deposits or eye symptoms due to the cornea being avascular. Cysteamine eye drops do help decrease corneal crystal density and associated symptoms, although to date, existing eye drop preparations require up to hourly instillation and are hence challenging for patient treatment adherence. Crystals found only in the corneal epithelium can sometimes be managed by removal of the outer corneal layers (superficial keratectomy).
Large Cornea: Megalocornea
Megalocornea is defined as a corneal diameter >12 mm at birth or >13 mm after 2 years of age in the absence of elevated eye pressure ( Fig. 64.5 ). It is usually bilateral and may be isolated or associated with other ocular or systemic disorders.
Isolated megalocornea is most commonly inherited in an X-linked recessive pattern (90%) and thus occurs mostly in males. It can be inherited in an autosomal recessive manner or very rarely in an autosomal dominant fashion. It is associated with several gene mutations including CHRDL1 (X-linked megalocornea), LTBP2 , SH2PXD2B , NOTCH2 , PIK3R1 , ZNF469 , and chromosome 16 duplication.
Clinical measurement of horizontal corneal diameter is diagnostic. It is important to rule out congenital glaucoma by measuring eye pressure, axial globe length, and refraction and assessing the ocular structures, especially corneal clarity and optic nerve cupping (all of which are affected in glaucoma but not megalocornea).
Intervention is not needed for isolated megalocornea, because it is nonprogressive. Dryness due to exposure can be treated with artificial tears. Treatment of associated ocular or systemic issues are determined by a multidisciplinary team.
Small Cornea: Microcornea
Microcornea is defined as a clear cornea of normal thickness with a diameter <9 mm at birth or <10 mm after 2 years of age ( Fig. 64.6 ). It is most commonly associated with other ocular findings such as cataract, coloboma, iris maldevelopment, retinal underdevelopment or outpouching, nystagmus, and/or ptosis. Various systemic findings such as skeletal, cardiac, genitourinary, and neurologic defects have been reported in association with microcornea.
Isolated microcornea is very rare. It is thought to represent an arrest of corneal growth after differentiation is complete in the fifth month age of gestation. Genetic association is poorly defined, , but mutations in PAX6 , CRYBB1 , ZNF408 , and WDR37 have been reported. It has been associated with an FBN1 mutation in one case of severe neonatal Marfan syndrome and bilateral ectopia lentis. In utero exposure to cytomegalovirus has also been implicated.
Clinical measurement of horizontal corneal diameter is diagnostic. Because it rarely occurs in isolation, further investigation to uncover associated ocular or systemic features is warranted. Eye pressure, portable slit-lamp biomicroscopy, and dilated fundus exam should be performed in the first few weeks of life. Further imaging, such as AS-OCT or UBM, may be advisable depending on clinical findings.
Isolated microcornea does not warrant intervention if the cornea remains clear. However, given the small anterior chamber, patients are at risk of glaucoma, so long-term eye pressure monitoring is advisable. Medical and surgical interventions will depend on associated findings.
Iris and Pupil: Congenital Abnormalities
Diffuse Iris Underdevelopment: Aniridia
Iris hypoplasia may be total (aniridia) or partial (coloboma). Although aniridia directly translates to absence of iris tissues, congenital aniridia is considered a panocular abnormality involving the iris, cornea, anterior chamber angle, lens, retina, and optic nerve ( Fig. 64.7 ). Of note, there is usually a small peripheral stump of iris tissue that is visible both on clinical exam and histologically. The most common accompanying ocular finding is cataract. Other lens changes (subluxation, coloboma, posterior lenticonus, and microspherophakia), corneal opacification, micro- or megalocornea, glaucoma, and foveal hypoplasia can co-occur with aniridia. Especially in cases with no family history, Wilms tumor must be ruled out. ,
Congenital aniridia prevalence is estimated to be 1 in 40,000 to 1 in 96,000 newborns. , It may be sporadic or inherited either in isolation due to PAX6 mutations or as part of Wilms tumor–aniridia–genital anomalies–retardation (WAGR) syndrome; the latter is due to 11p13 deletions that affect both PAX6 and adjacent WT1 genes. , Aniridia has also been associated with mutations in FOXC1 and CYP1B978-0-323-69415-5.
A complete ophthalmologic examination should be performed in the first few weeks of life. Cataract and glaucoma are seen at an early age, so regular monitoring of lens opacities and eye pressure is necessary. Genetic testing can be used for diagnosis confirmation, familial counseling, and early detection of children at risk for Wilms tumor. The nature of the PAX6 mutation and the degree to which PAX6 protein function is impaired influence disease severity. Some patients only have partial iris defects, no foveal hypoplasia, and relatively normal vision; others are more severely affected. Renal ultrasound can be obtained while awaiting genetic testing results.
Treatment will depend on the ocular findings. Refractive correction with protection for light sensitivity is advised. If eye pressure is raised it should be treated, initially with eye drops and often then with surgery. Cataracts can undergo removal as needed. Because both the anterior and posterior segments of the eye are often affected, visual impairment tends to be significant. Low-vision aids, educational accommodations, and multidisciplinary supervision are needed for long-term care.
Focal Iris Underdevelopment: Iris Coloboma
Iris coloboma classically presents as a keyhole-shaped iris defect ( Fig. 64.8 ). These defects most commonly involve the inferonasal iris and can be unilateral or bilateral, symmetric or asymmetric. They can occur in isolation or in conjunction with colobomas involving other ocular structures such as the ciliary body, choroid, retina, and/or optic nerve. If only the iris is involved, visual prognosis is usually good; patients can have glare/light sensitivity due to light scatter through the peripheral lens in the area of the iris defect, or occasionally double vision. If there is retinal or nerve involvement, vision may be more severely impaired and will depend on the size and location of the coloboma(s).
There are a number of syndromes associated with ocular colobomas. CHARGE syndrome is an acronym for coloboma of the eye, heart defects, nasal choanae atresia, growth/development retardation, genitourinary anomalies, and ear issues/deafness. Cat eye syndrome describes the vertical colobomas reminiscent of a cat pupil seen in these patients. Patau syndrome can include iris and/or retina/nerve colobomas as well as microphthalmia, Peters’ anomaly, cataract, retinal dysplasia, optic nerve hypoplasia, and nystagmus. Treacher Collins syndrome has classic facial features including iris colobomas, downslanting eyelid margins, ear anomalies, and/or micrognathia.
Ocular colobomas affect <1 in 10,000 births. They are usually caused by failure of the embryonic fissure to close in the fifth week of gestation and can be associated with mutations in PAX2. CHARGE syndrome is an autosomal dominant condition caused by mutations in CHD7. Cat eye syndrome is caused by trisomy/tetrasomy of part of chromosome 22. Patau syndrome results from trisomy of chromosome 13. Treacher Collins syndrome is caused by mutations in TCOF1.
Complete ophthalmologic examination in the first few weeks of life can help define the size and symmetry of iris colobomas and also identify any other associated ocular anomalies that may impact vision. If the eyes are asymmetrically involved, amblyopia can develop in the more affected eye, in which case early prophylactic therapy (e.g., patching) can be instigated. Eyes with additional colobomas may need further workup and/or treatment (e.g., chorioretinal colobomas can cause retinal detachment and may benefit from prophylactic laser to prevent a future occurrence or surgery to treat an existing one). Genetic testing can be used for diagnosis confirmation, familial counseling, and early detection in future pregnancies. Involvement of other services for systemic workup and management is important.
Treatment depends on the degree of involvement. Asymptomatic isolated iris coloboma(s) may only require observation. Light sensitivity can be treated with tinted glasses. Surgical repair of an iris defect may be possible by bringing together the two edges of the coloboma to create a more rounded pupil; this can help with both cosmesis and glare/light sensitivity and can be performed in young patients who still have their native lens. However, it may not be possible in patients with larger defects. If the ocular lens is involved (e.g., ciliary body colobomas can cause a focal lens zonular defect and resultant astigmatism), refractive correction should be used. Cataracts can undergo removal as needed. If vision is significantly impaired, low vision aids, educational accommodations, and multidisciplinary supervision may be necessary.
Diffuse Bilateral Iris Hypopigmentation: Albinism
Albinism encompasses a heterogenous group of inherited disorders that share a defect in melanin biosynthesis. Whereas cutaneous and/or iris hypopigmentation are obvious external signs, other less evident ocular features include underdevelopment of the central retina (foveal hypoplasia), resulting in delayed visual development, reduced vision, nystagmus, and eye misalignment ( Fig. 64.9 ).
Current classification is based on pathologic genes. X-linked ocular albinism is due to GPR143 mutations on Xp22.3, whereas autosomal recessive oculocutaneous albinism (OCA) is caused by mutations in genes encoding several different proteins (OCA1: tyrosinase; OCA2: P protein; OCA3: TYRP1A; and OCA4: SLC45A2). TYR mutations in OCA1 have a more severe effect on pigmentation (and hence phenotype) than mutations in the genes encoding GPR143 or P protein.
Iris transillumination defects can be evaluated by transscleral illumination with a pen-light placed directly on the bulbar conjunctiva or by directing a strong slit beam through an undilated pupil. In albinism, the thin iris will allow incident light to be reflected not only through the pupil but also through the iris itself. In preverbal children, visual acuity can be tested using Teller Acuity Cards. Cycloplegic refraction should be performed to determine refractive errors that require glasses correction. Retinal OCT can be used to show a lack of foveal umbo (the normal dip in the central retina required for good acuity). AS-OCT can demonstrate a thin iris, specifically the posterior epithelium. A special visual-evoked potential technique can be performed to show excess optic nerve fiber crossing at the chiasm that is highly sensitive for albinism. Absence of nystagmus, detectable depth perception, melanin pigment in the macula, and some degree of foveal reflex are predictors of better future vision.
Annual follow-up for patients under 16 years old is recommended to update their glasses prescription and ensure adequate filter for light sensitivity. Prosthetic iris implants are now approved by the US Food and Drug Administration and have shown better safety and effectiveness profiles in patients with albinism compared with other iris pathologies (e.g., trauma, aniridia, and uveitis), so they may be considered to reduce glare. Many children with nystagmus develop an abnormal head position where the nystagmus is least prominent and hence vision is best (null point). If the abnormal head position causes neck muscle issues or interferes with daily activities or socialization, surgery to bring the null point into the primary visual axis (i.e., straight ahead) can be performed (Kestenbaum-Anderson procedure). , This is often delayed until the infant is older to allow more accurate preoperative measurements. Oral levodopa (L-DOPA) therapy has proved beneficial in albino mice, , but a prospective randomized controlled trial failed to find benefit in humans.
Asymmetric Iris Pigmentation: Heterochromia ( Fig. 64.10 )
A difference in color between the two eyes at birth may be due to Waardenburg syndrome or congenital Horner syndrome. Waardenburg syndrome is defined by iris heterochromia, eyelid and tear drainage system abnormalities, narrow eyelid fissures (blepharophimosis), prominent broad nasal root, nasal eyebrow overgrowth, a white forelock, and deaf-mutism. Partial or complete iris heterochromia occurs in approximately 30% of patients. Waardenburg syndrome has four types (I, II, III, IV), of which type II is most commonly associated with iris heterochromia. , Congenital Horner syndrome presents with heterochromia, ptosis, miosis, and facial anhidrosis (reduced flushing on the affected side of the face during crying in neonates). ,