Developmental Anomalies of the Globe and Ocular Adnexa in Neonates

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.

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.