Background

Congenital anophthalmia and microphthalmia are rare defects of the globe resulting from abnormalities in the development of the primary optic vesicle. Anophthalmia has an incidence of 0.18–0.4/10 000 births1, 2 and microphthalmia around 1.5–19/10 000 births.2, 3 The term anophthalmia is used where there is no visible ocular remnant. However, ultrasound often reveals a buried microphthalmic remnant or cyst. Microphthalmia refers to an eye with reduced volume and may be associated with coloboma or with an orbital cyst. It may usefully be subdivided into microanterior segment (when the overall axial length may be normal or even increased), and microposterior segment, since each of these may have a different underlying aetiology. There is a spectrum of disease that exists between these conditions. Both anophthalmia and microphthalmia may be unilateral or bilateral, and over 50% may be associated with systemic abnormalities4 (and Ragge, unpublished data). In the case of unilateral anophthalmia or microphthalmia, there may be developmental anomalies of the other eye, including coloboma, lens, and optic nerve abnormalities.5, 6

Assessment in the neonatal unit

The management of a child presenting with suspected anophthalmia or microphthalmia benefits from the coordinated involvement of a multidisciplinary team of health care professionals. The initial assessment is likely to be carried out by a paediatrician and/or paediatric ophthalmologist in the neonatal period. Early examination by an ophthalmologist is crucial and will include both a diagnostic and visual assessment, leading to an early management plan. The initial meeting with the parents allows the ophthalmologist to explain both the condition and the likely management plan. The parents are likely to be deeply traumatised early on, especially if the findings were not predicted prenatally, and a discussion of diagnosis, if known, and likely aetiology and investigations is helpful at this stage.

An early paediatric assessment involves a full examination of the whole child to search for any associated systemic abnormalities. The child may already be known to have significant other medical problems, requiring active management even at this stage. Particular attention is focused upon the face, including ear and palate, the cardiac system, genital anomalies, feeding difficulties, which might indicate oesophageal abnormality, and metabolic disturbances, which may indicate pituitary underaction. A management or referral plan is then made depending on any systemic abnormalities identified.

Assessment in the eye clinic

As soon as possible in the first few weeks after birth, the child will be assessed in the paediatric eye clinic. If there are severe ocular anomalies, the assessment would be best carried out in the first 2 weeks of life. The history will focus on trying to make a diagnosis by establishing any other ocular or systemic features, and identifying aetiological factors, in particular any relevant gestational factors or family history of other ocular or systemic abnormalities. The diagnostic assessment confirms anophthalmia, microphthalmia, coloboma, orbital cyst, or other associated ocular pathology. It is important to examine both eyes since in cases of unilateral anophthalmia or microphthalmia the fellow eye may show other, more subtle, abnormalities such as coloboma, optic nerve hypoplasia, retinal dystrophy, or cataract. An ultrasound of the eye and orbit can be useful to determine the internal structure of the eye, the presence of an ocular remnant or cyst, where this is not immediately visible, and to determine axial length in cases of microphthalmia.

Vision is assessed using early paediatric vision tests, and electrodiagnostics if necessary. A flash visual evoked potential (VEP) will establish if any vision is present in cases of apparent anophthalmia or severe microphthalmia; a pattern VEP will both establish a level of acuity and detect any optic nerve dysfunction, and an electroretinogram will identify if there is retinal dysfunction.

Children with even quite severe microphthalmia may have some vision and it is important to establish this early on, especially in bilateral cases, as it will guide the approach to socket expansion (Figure 4).

Figure 4
figure 4

Girl with R extreme microphthalmia and left microphthalmia and coloboma wearing a right prosthesis to match the microphthalmic left eye.

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Investigations and screening

The child will need several investigations in addition to orbital ultrasound and electrodiagnostic testing. Since many conditions that affect ocular development also affect brain development, it is important to arrange imaging of the brain, particularly looking at midline structures, the hippocampus and periventricular structures. Magnetic resonance imaging (MRI) is preferable to computed tomography scanning since there is higher resolution of the structures of interest and no radiation exposure (important in conditions such as Gorlin syndrome). Renal ultrasonography is also recommended given the association between eye and renal anomalies. The paediatrician is also likely to have screened for intrauterine infections. Congenital rubella has long been associated with microphthalmia7 and it would be important to exclude this given an appropriate history during pregnancy. There have also been case reports of microphthalmia associated with other intrauterine infections such as varicella, Toxoplasma gondii, herpes simplex virus, and cytomegalovirus.8, 9, 10, 11 In addition, early assessment of hearing is particularly important to allow prompt intervention in the case of abnormality.

Examination of other family members for related ocular pathology such as anophthalmia or microphthalmia, anterior segment malformation, glaucoma, coloboma, retinal dystrophy, and optic nerve hypoplasia is important since this may provide a clue to likely diagnosis or inheritance pattern. Genetics assessment will include chromosome analysis and testing of particular genes. In our centre, we routinely carry out fine resolution chromosome analysis and screening of a wide range of genes on a research basis or in collaboration with various diagnostic laboratories.

Management

The management of children with anophthalmia or microphthalmia is often best achieved through a shared care approach between the local ophthalmic and paediatric services and a specialist centre. To maximise the visual potential of the child glasses are prescribed for any significant refractive error and, in the case of children with only one, sighted eye for protection.

Socket expansion

Early socket expansion is important to minimise facial deformity and can be started very soon after birth in cases of anophthalmia or severe microphthalmia. This is best carried out in a specialist unit with a good ocular prosthetic service available. The normal eye in a child at birth is approximately 70% of its adult size. By contrast, the face even by 3 months is only 40% of adult face size. There is, however, rapid growth of the face and by 2 years it is 70% of adult size and by 5.5 years 90% of adult size.12 Normal facial and orbital development is affected by reduction in ocular volume and in cases of anophthalmia and moderate or severe microphthalmia there is often underdevelopment of the bony orbit, the eyelids, and the fornices. Without intervention, the socket remains underdeveloped and the ability to wear a prosthesis in later life is compromised. In unilateral cases the asymmetry becomes more pronounced as the child grows. The cosmetic deformity that can ensue without intervention can lead to marked difficulties with social interaction. With appropriate treatment the cosmetic outcome is greatly improved (Figure 1, Figure 2, Figure 3, Figure 4, Figure 5, Figure 6, Figure 7).

Figure 1
figure 1

Girl with left microphthalmia (a) before socket expansion with cosmetic shell (b) view of microphthalmic eye (c) appearance wearing cosmetic shell over L microphthalmic eye.

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Figure 2
figure 2

Girl with L anophthalmia undergoing sequential socket expansion using solid shapes. Note initial slanting of L brow, which signifies a smaller L orbit, and subsequent symmetry of brows. (a) 5 months old, (b) 15 months old, (c) 21 months old, (d) 2 years 2 months old, (e) 3 years 10 months, (f) 5 years 3 months.

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Figure 3
figure 3

Two boys with R anophthalmia (a and c) as young babies before socket expansion using solid shapes and (b and d) demonstrating symmetrical socket appearance.

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Figure 5
figure 5

The results of socket expansion using hydrophilic expanders are seen in this girl with L anophthalmia (a) with hydrophilic expander in situ and (b) with first painted prosthesis.

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Figure 6
figure 6

(a) Girl with bilateral severe microphthalmia and no perception of light wearing bilateral prostheses. (b) Boy with clinical anophthalmia, but with light perception wearing clear prostheses.

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Figure 7
figure 7

Girl with L microphthalmia and cyst (a) cyst in situ acting as socket expander, (b) post-removal preserving the microphthalmic eye and wearing L painted prosthesis.

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Progressive growth of the socket can be facilitated by adding volume to the socket using socket expanders. Traditionally, this involved frequent visits to hospital for sequential socket expansion using progressively larger acrylic shapes with or without moulding of the socket under anaesthesia. However, more recently the use of hydrophilic expanders has allowed a relatively non-invasive start to the expansion process and a reduction in the number of initial visits to hospital needed to produce satisfactory socket expansion.13, 14 Hydrophilic expanders, for example those manufactured by Acri.Tec©, are available in several sizes and are placed, or sutured, in the socket, along with topical preservative-free antibiotic drops. The lids are then closed over the expander with a temporary tarsorrhaphy, secured either by suturing or with histoacryl glue. In our experience, glue is easier, can be performed in clinic under topical anaesthetic and leads to very few complications. A painted prosthesis is then introduced as appropriate (Figure 5). This is usually increased in size at regular intervals until symmetry is achieved or no more expansion is possible. In some cases, additional reconstruction, such as a primary orbital implant in anophthalmic, or severely microphthalmic, non-seeing eyes, may be necessary. This allows use of a smaller painted prosthesis, which is easier to insert and remove. The parents and eventually the child are taught how to manage the prosthesis, although frequent checks by an ocularist will continue to be needed.

In the case of microphthalmic eyes, especially where there is vision, the situation is a little different and management varies according to the centre. Where the microphthalmic eye has an axial length of less than 16 mm (Collin, unpublished observation), it is unlikely to promote normal orbital growth alone and it is therefore necessary to increase the socket volume early on to prevent asymmetry becoming more pronounced as the child grows. In this situation, a purpose-made cosmetic shell can be fitted over the microphthalmic eye or ocular remnant to promote orbital growth. Clear shapes will need to be fitted initially in the case of eyes with a positive VEP, or with a good-sized eye with a cornea. In bilateral cases, this will need to continue throughout life (Figure 6). Since hydrophilic expanders are translucent, they can be fitted in front of severely microphthalmic eyes with light perception without the fear of blocking out the vision. However, they cannot be used with moderately microphthalmic eyes since these need clear moulded shapes in front of them to avoid damage to the underlying eye (Figure 1).

Some centres will remove a non-seeing eye, and use a dermis fat graft/ball implant at an early stage. Our preference, however, is to preserve the microphthalmic eye even if there is no visual potential. The advantages of this approach are that the microphthalmic eye is likely to provide some stimulus to palpebral aperture and socket growth, especially where the microphthalmia is only mild or where there is an associated orbital cyst and it avoids the need for early invasive surgery with all its accompanying risks.15 A clear conformer is created and inserted, allowing the health of the underlying microphthalmic eye to be observed. Subsequently, when the fit is satisfactory, a hand-painted prosthesis can be made. In mild or moderate microphthalmia, this needs good clearance over the cornea. In severe unilateral microphthalmia, it will fill the available socket space.

When the axial length of the eye is over 16 mm, or if there is a large cyst present, the fitting of such a prosthesis is more optional, as orbital growth is more likely to be normal (although this should be kept under observation). The timing is then governed by social and aesthetic need, for example a good time to introduce a prosthesis might be just before the child starts school.

The question of when to change a clear prosthesis over a unilateral microphthalmic eye with some vision (such as light perception) for a painted prosthesis is difficult. A clear prosthesis allows the maximum visual potential of the microphthalmic eye to be reached and the health of the underlying eye to be checked. However, once a stable situation is reached, the vision is unlikely to be lost even if the microphthalmic eye is covered, and better cosmesis, and probably better vision and stability of the good eye will be achieved if a painted prosthesis is fitted (Figure 1).16

For patients with anophthalmia or microphthalmia and a large orbital cyst, gradual socket enlargement can usually be achieved using the natural expansion produced by the cyst (Figure 7). The parents may need gentle reassurance that this is the best policy as initially the appearances may be unsightly. Occasionally, the cyst may need to be drained because it has grown too rapidly. However, caution should be observed with this, since there is often a direct connection with the eye itself, and the cyst usually refills in any case. We find that by 2–4 years of age the sockets of most affected children have developed sufficiently for the orbital cyst to be removed. Before this surgery we perform an MRI of the orbits to assess the cyst size, and any potential connection to the brain. After cyst excision and, if necessary, orbital implant, the patients receive a temporary and subsequently custom made ocular prosthesis (Figure 7).

Long-term management

After the initial socket expansion over the first 5 years of life, the prosthesis and the socket will require review at least yearly. Microphthalmic eyes may develop angle closure glaucoma, which may cause loss of what vision does exist and can also cause pain.17 Children with chorioretinal coloboma and their parents should be aware of the increased risk of retinal detachment and receive instructions for prompt attendance in the case of any alteration in vision.18 Glasses are prescribed for refractive error, protection, and sometimes for providing lenses to minimise cosmetic defect (such as plus lenses to increase the size of a microphthalmic eye or prisms to equalise a height discrepancy).

Paediatric and genetic follow-up

Associated systemic abnormalities may have very major implications for the child and so may need considerable input from general or specialist paediatric services. In the case of bilateral anophthalmia or severe microphthalmia with no light perception, there may be a reversal of sleep pattern. In this situation, melatonin supplements at night may be very helpful to establish a regular nocturnal sleep pattern. Growth assessment is important since there may be associated pituitary abnormalities. Developmental assessment by a paediatrician skilled in assessing children with visual problems will detect any early difficulties, but can also provide welcome reassurance for parents, since there is a variance in developmental progress of visually impaired children compared with their sighted peers (www.earlysupport.org.uk) (see Table 2 and Table 3).

Table 2 The role of the ophthalmologist in management of suspected anophthalmia/microphthalmia
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Table 3 Three major questions most parents want to know
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It is important to reach an overall diagnosis if possible, since this will direct future management. The parents are usually keen to understand the nature of the condition, and a combined approach from paediatrics, ophthalmology, and genetics will help to achieve this. The parents may wish to receive genetic counselling regarding the risks of another child being affected, although in some cases, they may wish to wait. The high incidence of de novo mutations, mosaicism, and variable penetrance, combined with a large overlap in phenotype even among those with the same genetic mutation, makes genetic counselling very complex,19, 20 and we would always advise the ophthalmologist involved in the care of these children to involve an ophthalmic or medical geneticist.

Vision and family support

It is very important that any visually impaired child receives early help from vision support services. The child may qualify for a Certificate of Visual Impairment, which may help to expedite some of the services and financial support available. There are publications, such as ‘Show me what my child can see’ (available from the Wolfson Centre, Mecklenburg Sq, London WC1N 2AP) which can help parents to interact with their babies if visually impaired. Early intervention undoubtedly makes a huge difference to the overall development of the child and the emotional well-being of the family.

In addition to the more widely known organisations for the visually impaired, there are two British charities, the Eyeless Trust (www.eyeless.org.uk) and MACS (Microphthalmic and Anophthalmic Children's Society, www.macs.org.uk) who can offer specialist advice and family support to these children and their families. Other charities that can be very helpful to these children include VICTA (Visually Impaired Children Taking Action, www.victa.org.uk), VISION and LOOK (The National Federation of Families with Visually Impaired Children, www.look-uk.org).

Aetiology and genetics

The development of the eye is highly complex. It is determined by sequential and coordinated expression of eye development genes within the developing tissues. Although some individuals with anophthalmia or microphthalmia have relatives with other eye malformations, the frequent lack of clear Mendelian inheritance in these conditions has made identifying the genes for eye development very challenging. However, using a variety of techniques, some genes involved in anophthalmia or microphthalmia have now been identified (see Table 1). These include genes principally involved in ocular development, such as CHX10, many of which are involved in the development of substructures within the eye19, 21 and genes that are involved in eye and brain development including SOX2, OTX2, and PAX6.20, 22, 23, 24, 25, 26 Several syndromic genes are involved in developing other organs in addition to the eye, including CHD7, the gene for CHARGE syndrome27, 28 and PTCH, the gene for Gorlin syndrome.29 There is a complex interplay between the different eye development gene pathways, which allows their expression to be finely regulated5, 27, 30 and begins to explain why there is such an overlap of the phenotypes associated with mutations of each gene.

Table 1 Selected genes and syndromes associated with eye malformations
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