Microphthalmia is defined when a globe has a total axial length that is at least 2 standard deviations (SDs) below the mean for age. Most postnatal growth of the eye happens in the first 3 years, primarily during the first year of life. In adults, the lower limit of axial length is approximately 21.0 mm, whereas in children this must be based according to age (▶ Table 11.1). Corneal diameter normally goes from 9.0 to 10.5 mm in neonates and 10.5 to 12.0 mm in adults.

Severe microphthalmia refers to a corneal diameter less than 4 mm and axial length less than 10 mm at birth or 12 mm after the first year of life. Orbital imaging such as computed tomography (CT) or magnetic resonance imaging (MRI) can reveal remnants of ocular tissue, to rule out anophthalmia, although pathology of orbital tissues reveals remnant tissues not visible by imaging.

Microphthalmia may be unilateral or bilateral, occurring in any degree of severity. Coloboma is the most common associated malformation (▶ Fig. 11.1). Other concurrent findings may include persistent fetal vasculature, cataract, and a wide range of anterior segment dysgeneses. Glaucoma can enlarge a microphthalmic eye so that it becomes larger, thus misleading the examiner that microphthalmia is not part of the initial finding.

Coloboma refers to those ocular abnormalities that result from failure of closure of the optic fissure during embryogenesis. This can be seen as fundus and/or iris coloboma. As the embryonic fissure closes between 5 and 7 weeks of gestation, abnormalities may occur anywhere along its distribution. The primary abnormality is failure of the (retinal pigment epithelium) RPE to close. Without RPE, the underlying choroid/uvea is not induced to form and the overlying sensory retina is maldeveloped (intercalary membrane). Clinically one observes a sharply demarcated white typically inferonasal lesion that may or may not encompass the optic nerve and/or fovea. Absence of a fovea portends a worse prognosis, whereas it is difficult to give a visual prognosis based on the appearance of the optic nerve. There is often hyperpigmentation at the edges of the fundus coloboma. Coloboma may also be isolated to the optic nerve or the iris. Heterotopic muscle and gliosis can rarely be observed within an optic nerve coloboma (ONC). Persistent fetal vasculature and ectopia lentis may be seen with coloboma, the latter due to involvement of the ciliary body with deficient zonules, which may also result in a lens notch. Retinal detachment may be a complication of fundus coloboma, seen in approximately 2% of patients.

The estimated prevalence of coloboma is 0.14%. This condition is usually sporadic. Around 50% of patients have bilateral involvement. Most patients with ONC alone are sporadic, although there are autosomal dominant (AD), autosomal recessive (AR), and X-linked (XL) recessive cases. Although the underlying molecular mechanism is often unknown, PAX6 gene mutations have been identified in patients with large coloboma of the optic nerve, retina, and choroid, but most patients will not have PAX6 mutations.

11.2 Molecular Genetics

Molecular genetic testing might begin with chromosomal microarray (CMA), particularly when systemic findings are present. Chromosome aberrations can be found in approximately 25 to 30% of patients with microphthalmia. The most frequent include trisomy of chromosome 9, trisomy of chromosome 12, trisomy of chromosome 18, Wolf–Hirschhorn syndrome (deletion of 4p), deletion of 13q, del(14)(q22.1–23.2), deletion of 18q, del(3)(q26), duplication of 3q, duplication of 4p, and duplication of 10q.

Single-gene causes of syndromic microphthalmia include SOX2 (3q26; 15–20%), OTX2 (14q22; 2–5%), RAX (18q21; 3%), FOXE3 (1p33; 2.5%), BMP4 (14q22; 2%), PAX6 (11p13; 2%), BCOR (Xp11.4; 1%), CHD7 (8q12.2; 1%), STRA6 (15q24.1; 1%), and GDF6 (8q22.1; 1%). Less common genetic causes include CRYBA4, HCCS, HESX1, IKBKG, and SHH, among other genes. Isolated microphthalmia known loci are shown in ▶ Table 11.2.

Patients with SOX2 mutations or deletions of 3q27 region are characterized by microphthalmia that is often bilateral and severe. Other findings include brain malformations, esophageal atresia, cryptorchidism, micropenis, hypogonadotropic hypogonadism, pituitary hypoplasia, growth failure, delayed motor development, and learning disability. Molecular genetic testing finds a heterozygous SOX2 mutation in approximately 40% of patients with bilateral severe microphthalmia. It is AD, but most cases are due to de novo mutations. Complete penetrance and variable expressivity are typically seen.

Individuals with OTX2 mutations may have severe microphthalmia, with anterior segment dysgenesis, retinal dysplasia, and optic nerve hypoplasia. They may also have pituitary anomalies, brain anomalies, developmental delay, and autistic features. Patients with RAX gene mutations can present with microphthalmia, sclerocornea, and developmental delay.

Most ONC are sporadic. There are uncommon AD, AR, and XL recessive cases. In most patients, the underlying molecular mechanism is uncertain. PAX6 gene mutations have been identified in patients with large coloboma of the optic nerve, retina, and choroid, a bilateral remnant of hyaloid vessel proliferation and growth, and mental retardation. Inversely, most patients with ONC do not have PAX6 abnormalities.

11.3 Differential Diagnosis

11.3.1 True Anophthalmia

This represents a failure of optic vesicle formation, leading to complete histologic absence of ocular tissues. Orbital imaging such as CT or MRI can reveal remnants only or complete aplasia of an optic nerve.

11.3.2 Microcornea

Microphthalmia needs also to be distinguished from microcornea. The axial length of the globe is normal. Refraction depends on axial length. Inheritance can be AR or AD.

11.3.3 Posterior Microphthalmia

When microphthalmia primarily affects the posterior segment, the term posterior microphthalmia is used. The anterior segment is clinically normal. Additional findings may include macular folds and high hyperopia. This disorder overlaps with nanophthalmia.

11.3.4 Nanophthalmia

True nanophthalmia is a rare condition, in which the eye is affected after the closure of the embryonic fissure. Findings include high hyperopia, small-sized to normal corneas, shallow anterior chamber, glaucoma, cataract, normal fundus or retinal abnormalities (macular hypoplasia, foveal cysts, pigmentary degeneration), and a predisposition to peripheral choroidal effusion. Scleral thickness is increased. Three loci have been identified: NN01 (11p), NN02 (MFRP gene; 11q23), and NN03 (2q11-q14). One mutation in BEST1 has been associated with AD vitreoretinochoroidopathy and nanophthalmia.

11.3.5 Microphthalmia with Linear Skin Defects Syndrome (OMIM 309801)

Microphthalmia with linear skin defects (MLS) syndrome (OMIM 309801) is defined by unilateral or bilateral microphthalmia and/or anophthalmia and linear skin defects, frequently affecting the face and neck. These defects are present at birth and heal with time, leaving minimal residual scarring. Other findings may include developmental delay, heart defects, short stature, diaphragmatic hernia, nail dystrophy, preauricular pits, hearing loss, and genitourinary malformations. Linear skin defects have been reported in 95% of patients, and usually affect the face and neck. Xp22 monosomy or HCCS mutation are associated with MLS syndrome. It is inherited in an XL dominant (XLD) manner.

11.3.6 Gorlin–Goltz Syndrome (OMIM 305600)

Gorlin–Goltz syndrome is characterized by dermal hypoplasia and microphthalmia. Limb and skeletal malformations are commonly seen. The syndrome is caused by point mutations and deletions of PORCN.

11.3.7 Oculocerebrocutaneous Syndrome (OMIM 164180)

Oculocerebrocutaneous syndrome (OMIM 164180) is defined by orbital cysts and microphthalmia, focal skin defects, and brain malformations (polymicrogyria, periventricular nodular heterotopias, enlarged lateral ventricles, and agenesis of the corpus callosum).

11.3.8 Aicardi Syndrome (OMIM 304050)

Aicardi syndrome includes a triad of agenesis of the corpus callosum, typical chorioretinal lacunae, and infantile spasms. Microphthalmia, developmental delay, polymicrogyria, and costovertebral anomalies are also common. Refractory epilepsy and pigmentary lesions of the skin can be seen. This condition has been associated with the locus Xp22 and appears to be XLD by de novo mutations; however, the specific gene is unknown.

11.3.9 Lenz Microphthalmia Syndrome (OMIM 309800)

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