Disorders of the eye as a whole

Simple non-colobomatous microphthalmia

Simple microphthalmia refers to an otherwise structurally normal but small eye and has been used interchangeably with “nanophthalmos” (though the latter refers to a small eye with microcornea, axial length <18 mm, and ≥ 8D of hypermetropia, see below). Vision is variably affected, depending on the degree to which the eye is microphthalmic, associated high errors of refraction and consequent amblyopia, and complications in some cases of nanophthalmos such as a macular fold and uveal effusion or glaucoma. As microphthalmia and coloboma are regarded as eye abnormalities on a spectrum with possible shared pathophysiology, the distinction between the two is somewhat arbitrary and rarely are genes associated solely with simple non-colobomatous microphthalmia (see Table 16.1 ).

Colobomatous microphthalmia

Coloboma is the most common ocular malformation associated with microphthalmia and is found in syndromic and isolated forms of microphthalmia. Failure of the optic fissure to close during the 5th week of gestation results in uveal coloboma, affecting any combination of iris, choroid, retina, and optic nerve. A number of genes have been associated with recessively or dominantly inherited isolated colobomatous microphthalmia, including ABCB6 , ALDH1A3 , GDF6 , and SHH , and several more genes are associated with syndromic colobomatous microphthalmia (see Table 16.1 ). Some families demonstrate dominant inheritance of colobomatous microphthalmia and variable expression, with extreme microphthalmia at one end of the spectrum and small iris or fundus colobomas at the other. X-linked inheritance is documented with syndromic colobomatous microphthalmia, sometimes presenting with mental retardation, as in the case of BCOR or SOX3 mutation.

While coloboma frequently co-occurs with microphthalmia, it is commonly seen without microphthalmia and has an estimated prevalence of 1 per 5000 live births. COACH syndrome, characterized by cerebellar vermis hypoplasia, oligophrenia, ataxia, coloboma, and hepatic fibrosis, is one example of syndromic coloboma without microphthalmia or anophthalmia, and has been attributed to mutations in TMEM67 .

Syndromic microphthalmia

A large number of syndromes have been associated with MAC (see Table 16.1 ); 33%–95% of patients with anophthalmia and microphthalmia have associated systemic abnormalities, and microphthalmia can present with a variety of associated ocular anomalies, including anterior segment malformations such as Axenfeld Rieger syndrome or cataracts, especially in the context of chromosomal abnormalities, persistent fetal vasculature (PFV), aphakia, and multisystem syndromes such as the oculo-dento-digital syndrome. A small eye may be the result of severe, widespread intraocular disease including advanced retinopathy of prematurity, retinal dysplasia, and retinal folds.

Many patients with microphthalmia-associated syndromes, especially chromosomal disorders, are developmentally delayed or have cleft palate. We will only mention a few of these syndromes in this section, an extensive list with highlights of each condition is given in Table 16.1 .

One of the most common syndromic causes of colobomatous microphthalmia is the CHARGE syndrome (coloboma, heart abnormalities, atresia of the choanae, retardation of growth and development, genitourinary abnormalities, and ear/hearing abnormalities). Affected patients can also have cranial nerve abnormalities such as facial nerve palsy, craniofacial clefting, dysphagia/esophageal abnormalities, duplication of the thumb, and congenital brain abnormalities, particularly of the forebrain. Although most cases are sporadic, autosomal dominant transmission has been reported. Mutations in the Chromodomain Helicase DNA-Binding Protein 7 gene ( CHD7 ) are responsible for 60% of CHARGE cases, with unlikely genotype–phenotype correlation. CHD7 encodes a putative chromodomain protein widely expressed in the neuroectoderm and in neural crest cells during human development. Mutations in the Semaphorin 3E gene ( SEMA3E ) can also result in CHARGE syndrome.

The Temple–al-Gazali syndrome ( Fig. 16.5 ), also referred to as X-linked dominant microphthalmia with linear skin defects (MLS) syndrome, and also known as the microphthalmia, dermal aplasia, and sclerocornea (MIDAS) syndrome, results from mutation of the Holocytochrome C Synthase gene ( HCCS ) and maps to Xp22.2. Mutations in NADH-Ubiquinone Oxidoreductase 1 Beta Subcomplex 11 ( NDUFB11 ) gene have also been implicated. Patients have linear, irregular areas of skin aplasia, especially of the head and neck, microphthalmia with variable sclerocornea, and, sometimes, abnormal intelligence. The condition is lethal in XY males.

In Fryns “anophthalmia plus” syndrome , there is microphthalmia or anophthalmia, cleft lip or palate, and sacral neural tube defect.

The branchio-oculo-facial syndrome presents with ocular manifestations of colobomatous microphthalmia, nasolacrimal duct obstructions, orbital cysts as well as branchial cleft sinus defects and craniofacial abnormalities, and it has been attributed to mutations in Transcription Factor AP2-Alpha ( TFAP2A ). Other microphthalmia syndromes with facial defects include fronto-facio-nasal dysplasia ( Fig. 16.6 ), frontonasal dysplasia associated with mutations in Aristaless-Like Homeobox 1 ( ALX1 ), and the cerebro-oculo-nasal syndrome in which there is an association of anophthalmia/microphthalmia, abnormal nares, and central nervous system anomalies.

In Delleman syndrome there is an association of skin tags, punched-out lesions of the skin on the ears and elsewhere, mental retardation, hydrocephalus, brain malformations, and orbital cysts.

Microphthalmia also occurs in patients with GOMBO syndrome (growth retardation, microcephaly, brachycephaly, and oligophrenia).

The eyes can be small in some patients with the oculo-dento-digital (ODD) syndrome , which is characterized by bilateral digital anomalies ( Fig. 16.7 ) with cutaneous syndactyly of fingers and camptodactyly, thin nose with hypoplastic alae nasi and small nares, partial dental agenesis, enamel hypoplasia, and glaucoma. Patients with the less common recessive variety of ODD are more likely to have microphthalmia. The syndrome results from mutations in Connexin-43 ( GJA1 ). Iris cysts and anomalous retinal development may occur.

Waardenburg recessive anophthalmia syndrome includes microphthalmia with syndactyly, oligodactyly, and other limb defects, and mental retardation. It is caused by mutations in Sparc-Related Modular Calcium-Binding 1 ( SMOC1 ) and possibly Formin-Binding Protein 4 ( FNBP4 ).

Patients with the X-linked recessive Lenz microphthalmia syndrome have colobomatous microphthalmia with mental retardation, malformed ears, and skeletal anomalies. BCL6 Corepressor ( BCOR ), which maps to Xq27-q28, has been identified as a responsible gene, and the specific missense mutation c.254 C>T has been implicated. Mutations in N-Alpha-Acetyltransferase 10 ( NAA10 ), which maps to Xq28, have also been identified. Oculofaciocardiodental syndrome , presenting with microphthalmia as well as a spectrum of other anomalies, is also associated with BCOR mutations.

The autosomal recessive Warburg MICRO syndrome comprises microphakia, microphthalmia, characteristic lens opacity, atonic pupils, cortical visual impairment, microcephaly, developmental delay by 6 months of age, and microgenitalia in males. It is caused by Rab18 protein deficiency and may result from mutations in RAB3 GTPase-Activating Protein, Catalytic Subunit ( RAB3GAP1 ), RAB3 GTPase-Activating Protein, Noncatalytic Subunit ( RAB3GAP2 ), Ras-Associated Protein Rab18 ( RAB18 ), and TBC1 Domain Family, Member 20 ( TBC1D20 ).

Microphthalmia has been uncommonly described in Rubinstein-Taybi syndrome , in which patients can have mental retardation, delayed growth, as well as characteristic craniofacial abnormalities, and is associated with mutations in CREB-Binding Protein ( CREBBP ). Other ocular abnormalities may be present as well, including corneal abnormalities, glaucoma, and optic nerve coloboma/dysplasia.

For a complete search of inherited conditions associated with microphthalmia and anophthalmia, consult Online Mendelian Inheritance in Man (OMIM) at http://omim.org/ .

Microphthalmia with orbital cyst

Patients with this form of microphthalmia present with a congenital bulge behind the lower lid ( Fig. 16.8A ). There is a failure of optic fissure closure and the protrusion of a cyst from the posterior coloboma. It can be confused with a congenital cystic eye, but in the latter, the eye is replaced by a cystic structure without lens or other defined eye structures. In microphthalmia with cyst, the small eye is sometimes difficult to visualize and a neoplasm may be suspected. The cyst usually communicates with the eye. Ultrasonography and computed tomography (CT) or magnetic resonance imaging (MRI) aid in diagnosis ( Fig. 16.8B ). Most cases of microphthalmia with cyst are sporadic; familial cases have been reported, with presumed autosomal recessive inheritance.

Management is initially conservative, especially for small cysts. Large cysts may be managed with repeated aspiration or by surgical removal. If the cyst is not growing rapidly, it may be left in place until some orbital growth is achieved. Because the cyst communicates with the eye, its removal may deflate the microphthalmic eye, necessitating the removal of the latter.