KEY POINTS
- 1.
Major structural abnormalities of the eye in neonates include anophthalmos (no ocular tissues), microphthalmos (small, disorganized eye), nanophthalmos (small but relatively normally structured eye), and buphthalmos (whole eye is enlarged).
- 2.
Major eyelid defects in neonates include complete fusion of the upper and lower eyelids and a “hidden” eye (cryptophthalmos), focal fusion of the upper and lower eyelids (ankyloblepharon), focal defects in either or both eyelids (eyelid coloboma), or abnormal shape of the lower eyelid (euryblepharon).
- 3.
Causes of a narrowed palpebral fissure (space between the eyelids) with or without upper eyelid drooping (ptosis) in neonates include blepharophimosis, congenital ptosis, or congenital Horner syndrome.
- 4.
There are a number of known genetic causes for many of the above disorders, which are discussed throughout the chapter. In some cases these anomalies may occur sporadically and/or in isolation, whereas in other instances they may point to and help guide workup of a number of underlying systemic conditions.
- 5.
Management is challenging and case dependent. Consultation with an ophthalmologist is advisable prenatally if the condition is identified on prenatal imaging or soon after birth. Overarching principles include creating a clear visual axis to optimize visual development and restoring functional eyelids to help cover the eye and avoid corneal scarring and/or exposure.
Introduction to the Eye and Adnexal Structures
The upper eyelids form by fusion of the medial and lateral frontonasal processes, whereas the lower eyelids form by fusion of the medial nasal and maxillary processes. The eyelids play a critical role in protecting the eye from mechanical injury, generating some components of the tear film, and opening and closing to facilitate tear distribution and adequate hydration of the cornea and conjunctiva. Each eyelid contains a fibrous plate called a tarsal plate that gives it structure and shape. The tarsal plates contain Meibomian glands, which open onto the surface at the eyelid margin; these produce an oily secretion that covers the aqueous layer of the tear film generated by the lacrimal glands and reduces evaporative tear loss. The inner side of the tarsus and the anterior white of the eye (sclera) are lined by conjunctiva, a mucous membrane that provides protection and lubrication to allow the eyes to move smoothly under the eyelids. The outer aspect of the tarsus is covered by the orbicularis oculi muscle, which permits blinking. The superior aspect of the tarsus attaches to the levator and Muller’s muscles, both of which contribute to eyelid opening. The orbicularis muscle and lacrimal gland are innervated by the seventh cranial nerve. The levator muscle is innervated by the third cranial nerve and the Muller’s muscle by the sympathetic nervous system.
The anterior segment of the eye includes the cornea, iris, ciliary body, and lens. The lens develops from surface ectoderm, whereas the cornea has both surface ectoderm and neural crest components. The iris and ciliary develop from both neuroectoderm and neural crest, whereas the drainage angle is neural crest in origin. Light enters the eye through the cornea and is refracted by both the cornea and the lens to help focus it on the retina at the back of the eye. The pupil alters in size to allow more or less light into the eye, depending on ambient illumination. The iris contains radial (dilating) and circular (constricting) muscles that adjust the size of the pupillary aperture. The ciliary body produces aqueous humor that flows from behind the iris through the pupil and to the anterior chamber and drains into the anterior chamber angle (i.e., trabecular meshwork). A delicate balance between production and drainage of aqueous humor maintains the intraocular pressure within normal limits. Light that has passed through the cornea, aqueous humor, and lens makes its way through the vitreous humor in the vitreous cavity to the retina at the back of the eye. Photoreceptors in the retina receive the light, convert it to an electrical signal, and transmit it to the brain via the optic nerve.
Developmental anomalies can occur in each of these structures. This chapter will focus on those that are identifiable on fetal imaging, apparent during standard clinical examination by a nonophthalmologist in the neonatal period, and/or are important enough to cause functional consequences if not recognized early and referred for further evaluation.
Abnormal Eye Structure
Absent or Small Disorganized Eye: Anophthalmos and Microphthalmos ( Fig. 63.1 )
Clinical Features
Anophthalmos and microphthalmos encompass a spectrum of disease ranging from a complete absence of ocular tissues (anophthalmos) to a variable reduction in the size of the eye and degree of disorganization of the ocular structures (microphthalmos). In both conditions, the adnexal elements (brow, eyelids, palpebral fissure, and eyelashes) remain normal. Primary anophthalmos is extremely rare and patients clinically suspected of having this usually have some rudimentary structures present. Microphthalmos can be associated with uveal (iris, ciliary body, and choroid) and/or optic nerve colobomas. In some instances, a cyst may form through the area of defective closure (microphthalmia with cyst) (see Fig. 63.1 ). In these patients, the eye may be displaced superiorly with bulging of cysts in the inferior lid.
Systemic abnormalities co-occur with both conditions. Up to 90% have associated conditions such as amniotic band sequence, C oloboma of the eye, H eart defects, A tresia of the choanae, R estriction of Growth and development, and E ar abnormalities and deafness (CHARGE) syndrome, Meckel-Gruber syndrome, V ertebral defects, A nal atresia, C ardiac defects, T racheo- E sophageal fistula, R enal anomalies, and Limb abnormalities (VACTERL) association, and less-defined musculoskeletal, cardiovascular, and central nervous system anomalies. Genetic counseling should be considered, because there is approximately a 10% chance of either anophthalmos or microphthalmos presenting in a sibling. This is more likely in those with bilateral disease and those who have optic fissure closure defects or colobomas.
Pathophysiology
The incidence of microphthalmos is 10 to 11 in 100,000, and of anophthalmos, 1 to 2 in 100,000. – There is no sex predilection; however, risk increases with greater maternal age. , Both can be seen in the setting of trisomy 13 or 18. Only a minority (10%–20%) of cases have an identifiable genetic cause. , Mutations in SOX2 are the most common cause of bilateral and severe anophthalmos. Relatively consistent systemic associations with SOX2 mutations include learning disability, seizures, brain malformations, specific motor abnormalities, male genital tract malformations, mild facial dysmorphism, and postnatal growth failure. Sensorineural hearing loss has been described more recently. Mutations in STRA6 , ALDH1A3 , VSX2 , RAX , and FOXE3 have been implicated in consanguineous families with bilateral eye disease, with VSX2 mutations being specific to individuals of Middle-Eastern descent.
Evaluation
Ophthalmologic assessment should ideally be done in the first 2 weeks of life, especially if there are severe ocular anomalies. Functional determination of visual potential using electrophysiology can be performed when visual assessment is limited by age. Visual function does not always correlate with phenotypic findings, but vision is important in guiding treatment.
Magnetic resonance imaging (MRI), computed tomography (CT) scan, and/or ultrasound can confirm the absence of ocular tissues or determine abnormalities in those that are present. MRI and CT offer the advantage of simultaneously imaging cranial structures. Although CT imaging avoids the use of general anesthesia, MRI offers higher-resolution images with the ability to detect possible communication between a cyst and the brain. Ultrasound has the advantage of being quick and noninvasive and has been shown to detect microphthalmia as early as 18 weeks in utero.
Management
Management focuses on increasing the socket volume in the first 2 to 4 years of life. A microphthalmic eye with an axial length of less than 16 mm is not likely to promote orbital growth resulting in facial asymmetry. Multiple orbit expanders are used, including hard spherical implants, inflatable soft-tissue expanders, hydrogel osmotic expanders, and dermis-fat graft implants. Each have advantages and disadvantages. Hard spherical implants require multiple returns to the operating room to be replaced as the patient grows. Inflatable and self-inflating expanders are at risk of extrusion. Dermis-fat grafts grow with the child but require a second surgical site for harvest and have the risk of atrophy before achieving adequate orbit size.
Eye-socket conformer or prosthesis use can maintain socket shape. Caregivers must be counseled as to the importance of continuous use, because unnecessary removal may lead to contracture of the fornix. Prosthesis use is not as critical if there is a large orbital cyst (>16 mm) because this will also maintain orbital volume. At approximately age 4 years, when the orbit has fully matured, the cyst may be excised and a permanent orbital implant may be placed. Close follow-up is necessary throughout life for these patients. Microphthalmic eyes are prone to developing angle-closure glaucoma, resulting in vision loss and pain.
Small but “Normally Structured” Eye: Nanophthalmos ( Fig. 63.2 )
Clinical Features
In contrast to microphthalmos, in which the eye is small and its contents are disorganized, nanophthalmos refers to a small eye with (relatively) normally structure. Eye growth is compromised after the embryonic fissure has closed. Because the eye does not grow to a normal size, it typically exhibits a high degree of far-sightedness (hyperopia) , and is at a greater risk of angle closure glaucoma (because the anterior segment drainage angle is narrower than normal) and ocular surgical complications (e.g., intraoperative expulsive hemorrhage, choroidal effusion).
Due to its small size, the eye usually appears deeply set in the orbit (enophthalmos), with mild ptosis due to the upper eyelids hanging down over the eyes. The cornea can often be smaller than normal (microcornea) but not always. Various retinal abnormalities have been documented, including underdevelopment of the fovea (the part of the retina which permits good vision), schisis-like changes, midperipheral yellow spots, and pigmentary retinal degenerative changes. Patients can develop unilateral or bilateral amblyopia, nystagmus, and/or turning in of the eyes (esotropia), the latter of which can often be improved with glasses.
Pathophysiology
Nanophthalmos is usually bilateral and symmetric in most cases and can be inherited in a sporadic, autosomal dominant, or autosomal recessive manner. Two loci have been identified for autosomal dominant nanophthalmos (NNO1 and NNO3), , whereas the autosomal recessive form can be caused by mutations in the MFRP gene at the NNO2 locus. MFRP is expressed predominantly in the retinal pigment epithelium in humans and only after approximately 20 weeks of gestation, which is relatively late during ocular development, consistent with the relatively normal structure of these eyes. Nanophthalmos can be associated with a number of syndromes including autosomal dominant vitreoretinochoroidopathy, oculo-dento-digital dysplasia syndrome, and Kenny-Caffey syndrome (see below).
Evaluation
Patients should undergo a complete ophthalmologic exam in the first few months of life. This should include axial length, corneal diameter, refraction, slit-lamp examination of the anterior segment, dilated fundus exam of the retina, and ideally gonioscopy of the anterior segment drainage angle (only possible in older children and adults, unless under anesthesia). Optical coherence tomography of the retina can help delineate subtle retinal changes in the macula. Electroretinography can identify varying degrees of scotopic (rod-mediated) or photopic (cone-mediated) retinal dysfunction. Patients require long-term follow-up because some of the complications, such as angle-closure glaucoma, may not appear for several decades.
In the absence of syndromic involvement, nanophthalmos is not typically associated with systemic findings, although there is a report of its coincidence with cryptorchidism. Autosomal dominant vitreoretinochoroidopathy with nanophthalmos is caused by mutations in the BEST1 gene and usually manifests ocular findings. Patients with oculo-dento-digital dysplasia syndrome present with syndactyly and/or camptodactyly of the fingers, aplasia or hypoplasia of the middle phalynx of the fifth fingers and toes, tooth enamel hypoplasia, and a narrow nose. It usually shows autosomal dominant inheritance and is caused by mutations in GJA1 , which encodes connexin-43, a protein involved in channel assembly or conductivity. Patients with Kenny-Caffey syndrome can show proportionate growth retardation, macrocephaly, and episodic hypocalcemia with hyperphosphatemia. , Patients with the recessive form may also have mental retardation, microcephaly, micrognathia, cryptorchidism, and small hands/feet. ,
Management
The high to extreme degree of hyperopia usually seen in patients may be correctable with high-power glasses. This can result in moderate to good visual acuity but should be corrected beginning early in life because it can be very amblyogenic. Refractive correction with glasses may also help with the strabismus that these patients develop because their eyes often turn in as a result of them having to accommodate so hard to see even at distance. Residual esotropia not correctable with glasses may require surgery. Depending on the vision in each eye, patients may require amblyopia treatment, including patching and optical and/or pharmacologic penalization. These patients are at risk of lifelong eye issues, including angle closure glaucoma and spontaneous, intraoperative, or postoperative choroidal congestion, choroidal detachment, and/or exudative retinal detachment, so they should be counseled accordingly and followed chronically.
Enlarged Eye: Buphthalmos
A diffusely enlarged eye with an enlarged cornea most commonly is due to congenital glaucoma (please see the glaucoma chapter for further information).
Abnormal Eyelid Structure/Function
Absence of Eyelids, Adnexal Structures, and “Hidden Eye”: Cryptophthalmos ( Fig. 63.3 )
Clinical Features
In the “complete” form of cryptophthalmos, skin extends from the forehead to the cheek with no recognizable adnexal structures, including brow, eyelids, eyelid margin, eyelashes, meibomian glands, tear glands, or tear ducts. The eye is usually hidden underneath the skin and is often malformed, ranging from defects in the anterior chamber to the whole eye. There are also “incomplete” forms that show varying degrees of residual adnexal structures, but these too are usually associated with significant ocular malformations. Cryptophthalmos can also occur rarely in isolation, in which the eyelids and all adnexal structures form but are abnormal.
Pathophysiology
The isolated form can be inherited in an autosomal dominant fashion. More commonly, cryptophthalmos is inherited in an autosomal recessive manner and occurs in conjunction with systemic abnormalities as part of cryptophthalmos syndrome, cryptophthalmos-syndactyly syndrome, or Fraser syndrome. Systemic features include mental retardation, dyscephaly with skull malformations, and/or anomalies of the ears, nose, larynx, digits, kidneys, or genitals. , Fraser syndrome can be caused by mutations in FRAS1 or FREM2 , which are thought to encode putative extracellular matrix proteins that interact with and stabilize epithelial basement membranes.
Evaluation
Ophthalmologic assessment should be performed in the first few weeks of life to determine the visual potential. The skin directly overlying the eye can show a small depression, and sometimes a response to bright light can be observed (in the form of periocular muscle contraction). In its more complete forms, visual prognosis is usually very guarded, even if a response to light is observed. MRI, CT, ultrasound, and electrophysiology (visual evoked potential [VEP] and electroretinography) can be used to determine the visual potential.
Management
If visual potential can be demonstrated, surgical intervention can be considered. The goals of surgery are to create a clear visual axis to optimize vision and some sort of functioning eyelids to help cover the eye and avoid corneal exposure. Success depends on the extent of preexisting ocular malformation and adnexal structures. Full-thickness corneal transplants tend to do poorly due to the absence of conjunctiva and a normal ocular surface. An artificial cornea (keratoprosthesis) can be a choice, although these carry their own substantial risks.
Focal Eyelid Defect: Coloboma ( Fig. 63.4 )
Clinical Features
Coloboma is a full-thickness defect in the eyelid due to failure of the mesodermal folds to fuse correctly during development. Severity ranges from a small notch at the eyelid margin to near absence of an eyelid. It can be unilateral or bilateral and can involve the upper, lower, or both eyelids. The defect can be triangular or rectangular, with the eyelashes and tarsal plate typically being absent in the affected area. The majority of defects involve the upper eyelids, are usually more nasal, and are at greater risk of corneal exposure. Lower-eyelid defects are less common, more temporal, and have a lower risk of corneal exposure. Nasal lower-eyelid defects are often associated with tear-drainage-system (nasolacrimal) defects.
Pathophysiology
Eyelid colobomas can occur in isolation or as part of a craniofacial syndrome such as Goldenhar or Treacher Collins ( Fig. 63.5 ). Goldenhar syndrome is caused by defects in structures derived from the first and second branchial arches and first branchial cleft. Features include upper-eyelid coloboma in up to 20% of patients, limbal epibulbar dermoids, preauricular skin tags, deafness, small ears, and vertebral anomalies. , Congenital cranial nerve dysinnervation issues (e.g., Duane syndrome) are also more common in Goldenhar syndrome than in the general population. Treacher Collins syndrome is inherited in an autosomal dominant manner, is caused by mutations in TCOF1 that lead to impaired neural crest precursor development, and represents the most extensive developmental abnormality of the first branchial arch. Features include lower-eyelid colobomas in 75% of patients, downward-sloping palpebral fissures, mandibular and malar hypoplasia, malformed external ears, deafness in 50% of patients, unusual hair growth patterns, and normal intelligence.
