Microphthalmia is one stage in a spectrum of developmental abnormalities that affect the eye, with coloboma at the milder end and anophthalmia at the severe end. Collectively the eye defect is known as MAC (microphthalmia, anophthalmia, coloboma). Although microphthalmia and anophthalmia can present as isolated findings, they are more commonly appreciated as part of syndromes involving multiple malformations (Bronshtein et al., 1991). Both are associated with abnormalities of the central nervous system.

Warburg (1993) proposed a phenotypic classification of microphthalmia that consists of three groups: genetic (monogenic and chromosomal), prenatally acquired (teratologic agents and intrauterine deformations), and associations. Genetic disorders commonly result in malformations of the eye, whereas prenatally acquired insults result in disruption or deformation of an initially normal eye.

The eye derives from three embryologic germ layers. Neuroectoderm gives rise to the optic vesicle; neural crest cells are responsible for migration to the anterior chamber of the developing eye. Ectoderm is responsible for the formation of the lens placode. Neuroectodermal and mesodermal cells participate in the closure of the optic fissure. The variety of cells and tissue types involved explains variability of phenotypic abnormalities of the eye (see Table 29-1) (Warburg, 1993). The embryonic optic fissure is formed from invagination along the inferior aspect of the optic cup and optic stalk at the 5-to-8-mm stage of gestation. This fissure allows the ingress of the hyaloid artery and egress of retinal axons through the optic nerve. In the normal eye, the embryonic optic fissure closes at 33 to 44 days after conception. If the fissure fails to fuse, a defect in the neuroectodermal and uveal tissues will be produced, forming a coloboma. The coloboma is a layer of sclera lined by maldeveloped neuroectoderm (Leatherbarrow et al., 1990). Colobomas of the uvea are frequently associated with microphthalmia and microcornea. Congenital cystic eye is a malformation that results from failure of invagination of the optic vesicle. Cysts frequently develop from proliferation of neuroectodermal tissue at the edge of the persistently open embryonic fissure. The optic cup originates from localized evagination of forebrain. The optic cup is the supporting framework for further optic development. Thus, conditions that result in abnormalities of the forebrain also potentially affect the optic cup (Weiss et al., 1989).

Microphthalmia is a deformity that results from arrest of ocular growth and development. The eye is considered microphthalmic at birth if its greatest diameter is smaller than 15 mm. The normal newborn eye has a diameter of 16 to 19 mm (Price et al., 1986). Anophthalmia results from a failure in development or early involution of the primary optic vesicle during the 2nd or 3rd week of gestation. In degenerative anophthalmia, the optic tract and vesicles develop normally initially, but subsequently undergo degeneration and result in severe microphthalmia. Because the lens depends on the optic vesicle for its differentiation, it is usually absent. In anophthalmia, the non-neuroectodermal structures are usually normally formed. Thus, the orbits, eyelids, cilia, lacrimal apparatus, conjunctiva, and extraocular muscles are usually normal (Figure 29-1).

A national birth registry in the United Kingdom noted a prevalence of either anophthalmia or microphthalmia of 1.0 per 10,000 births (Busby et al., 1998). Thirty-four percent of affected infants had mild microphthalmia. Of the severely affected infants, 51% of cases were bilateral, other non-eye malformations were present in 65% of cases, and 72% had other eye malformations.

A Swedish health registry covering births during the years 1965 to 2001 observed a rate of 1.5/10,000 births for microphthalmia and 0.2/10,000 births for anophthalmia. Approximately 10% of the 432 children identified in this study had a chromosome abnormality (Källén and Tornquist, 2005). A recent epidemiologic study performed in California showed a twofold relative risk of bilateral anophthalmia if maternal age was 40 or more or if there was a multiple gestation (Shaw et al., 2005). After adjusting for other study factors, the relative risk was substantially lower if the mother has >12 years of education.

The ability to measure the human fetal eye and orbits antenatally was first documented in 1982, when in two separate reports, sonographic measurements of fetal ocular diameters, interocular distance, and binocular distance were published (Jeanty et al., 1982; Mayden et al., 1982). Using transvaginal sonography, Bronshtein et al. (1991) detected fetal eyes within their orbits in 40% of screened fetuses at 11 weeks of gestation and 100% of fetuses at 12 weeks of gestation. They also noted the presence of a hypoechogenic ring that represented the fetal lens in 75% of fetuses at 12 weeks and 100% of fetuses at 14 weeks of gestation. Fetal eyelid motion was detectable by the beginning of the second trimester. This group recommended that the optimal section for the examination of the fetal eye is a transverse plane taken at the level of the skull at the orbits. An oblique tangential section taken from the fetal nasal bridge may detect hypoechogenic circles lateral to the nose consistent with the developing lens (Bronshtein et al., 1991).

Nomograms have been established for measurements of the fetal eye taken from 12 to 37 weeks of gestation using a combination of transvaginal and transabdominal high-resolution ultrasound techniques (Achiron et al., 1995). In this study, the fetal eye was evaluated by a coronal–facial view with the ultrasound probe positioned lateral to the fetal orbit. This group measured the transverse and superoinferior diameters of the vitreous, and the outer-edge to outer-edge measurement of the lens as a function of gestational age. Only one observer made the measurements, but three separate measurements were obtained on each fetal eye. An intraobserver variation of 3.1 ± 1.5% existed. This group studied 12 fetuses at risk for eye abnormalities and found 3 with vitreous and lens measurements above or below the 95% confidence intervals for gestational age (Achiron et al., 1995). An additional study documented the normal growth percentiles for inter-malar and interethmoidal distances from 10 to 40 weeks of gestation (de Elejalde and de Elejalde, 1985).

Although routine study of the fetal face with prenatal sonography is recommended by most professional organizations, current guidelines do not recommend routine views of the fetal orbits or eyes (American College of Obstetricians and Gynecologists, 2008). Microphthalmia, even in the setting of a fetal face examination, may be difficult to detect antenatally. Bronshtein et al. (1991) reported two false-negative results for fetuses at prior genetic risk for microphthalmia. The sonographic diagnosis of anophthalmia can be equally challenging. Abnormalities in the fetal orbits are more easily recognized than abnormalities in the fetal globe. A specific finding appears to be flattened or concave eyelids when the fetal globes are missing (Figure 29-2).

The major consideration in the differential diagnosis is to determine whether the eye defects are isolated or part of a syndrome or association. Table 29-2 lists the etiologic classification of MAC. If the condition is isolated, it is important to determine whether other family members are also affected. Many chromosomal abnormalities include eye defects as part of a multiple congenital anomaly syndrome; trisomy 13 is one of the more common ones (Allen et al., 1977). MAC can be the consequence of exposure to certain drugs, ionizing radiation, or infectious agents. MAC can also be due to single-gene multiple congenital abnormality syndromes (Table 29-3), including Walker–Warburg syndrome (Crowe et al., 1986; Dobyns et al., 1990), Fraser syndrome (Schauer et al., 1990; Berg et al., 2001), Meckel–Gruber syndrome (Bateman, 1983), cerebro-oculo-facio-skeletal syndrome (Paladini et al., 2000), Lenz syndrome (Traboulsi et al., 1988), focal dermal hypoplasia (Goltz syndrome) (Gottlieb et al., 1973), Norrie disease, Hallermann–Streiff syndrome, oculodentodigital syndrome, frontonasal dysplasia, Fryns syndrome (Pierson et al., 2004), and microphthalmia with linear skin defects (Morleo et al., 2005). Any fetus diagnosed with MAC should have consideration of specific studies performed to rule out holoprosencephaly (see Chapter 14; Artman and Boyden, 1990). MAC can result from masses, such as encephalocele and tumors, pressing on the developing eye. Finally, MAC is seen in associations of congenital anomalies, such as CHARGE and VATER.